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  • 301.
    Sundelöf, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    AIR AND FIRE Carl Wilhelm Scheele, Torbern Bergman, The Royal Society of Sciences and the Discovery of Oxygen in Uppsala in the year 17722009In: OXYGEN TRANSPORT TO TISSUE XXX, 2009, p. 1-6Conference paper (Refereed)
  • 302.
    Sundström, Ingela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arts, Joris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    In vivo investigation of brain and systemic ketobemidone metabolism2010In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 135, no 2, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Ketobemidone metabolites have previously been identified in urine and plasma; here we show, for the first time, that norketobemidone and ketobemidone N-oxide are present in in vivo microdialysate from rat brain (striatum) after reverse microdialysis, suggesting striatal metabolism of ketobemidone. Ketobemidone metabolites were also identified in in vivo microdialysate samples from brain and blood, as well as in urine from rats, after subcutaneous administration of ketobemidone. Three Phase I metabolites (norketobemidone, ketobemidone N-oxide and hydroxymethoxyketobemidone) and three Phase II metabolites (glucuronic acid conjugates of ketobemidone, norketobemidone and hydroxymethoxyketobemidone) were identified in the microdialysates after subcutaneous administration. Coupled capillary liquid chromatography tandem mass spectrometry (LC-MS/MS) and SPE (boronate)-MS/MS were utilized for the analysis of the biological samples. The Phase I metabolites were identified by comparing the retention times and tandem mass spectra of the microdialysates with synthetic standards. The Phase II metabolites were identified by determination of exact masses and by comparing the tandem mass spectra of the microdialysates with those of synthetic standards for the aglycones. Hydroxyketobemidone, a catechol-type Phase I metabolite, was selectively isolated by solid-phase boronate-complexation but identified in urine alone. This work demonstrated that the in vivo microdialysis technique in combination with LC-MS/MS can be used to study the local metabolism of a drug in the brain.

  • 303.
    Svahn, K. Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Goransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Larsson, D. G. J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Chryssanthou, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    The search for new antibiotic substances from filamentous fungi2012In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 78, no 11, p. 1162-1162Article in journal (Other academic)
  • 304.
    Svahn, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Analysis of Secondary Metabolites from Aspergillus fumigatus and Penicillium nalgiovense: Antimicrobial Compounds from Filamentous Fungi Isolated from Extreme Environments2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the cultivation and extraction of filamentous fungi isolated from extreme environments in the search for new antibiotic compounds. Filamentous fungi are a rich source of medicines including antibiotics, and it is believed that many currently unknown fungal species and bioactive fungal metabolites remain to be discovered.

    Aspergillus fumigatus and Penicillium nalgiovense strains were isolated from an antibiotic-contaminated riverbed near Hyderabad, India, and soil taken from a penguin’s nest on Paulete Island, Antarctica, respectively. It was anticipated that the extreme conditions within these environments would exert unusual selective pressures on their filamentous fungi, possibly causing the secretion of new bioactive compounds.

    The cultivation, extraction and analysis of metabolites from the A. fumigatus strain resulted in the isolation of the antimicrobial substance gliotoxin. Subsequent investigations revealed that this strain’s secretion of gliotoxin was increased by as much as 65 % when it was cultivated in the presence of pathogen-associated molecular patterns. These results indicate the existence of a fungal receptor/signaling system for detecting nearby bacteria. The scope for using gliotoxin and the related metabolite bis(methyl)gliotoxin as biomarker metabolites for diagnosing the lethal pulmonary condition invasive aspergillosis was also investigated. Bronchoalveolar lavage fluid from 42 patients with and without possible invasive aspergillosis was extracted and analyzed. The results obtained suggest that gliotoxin and bis(methyl)gliotoxin are not suitable markers for diagnosing invasive aspergillosis.

    Studies on the P. nalgiovense strain from Antarctica resulted in the isolation of the antifungal agent amphotericin B. The secretion of this compound increased when P. nalgiovense was cultured on a potato-dextrose agar enriched with coconut flakes rather than liquid RPMI 1640 medium. This was the first time amphotericin B was isolated from any organism other than the bacterium Streptomyces nodosus.

    The results presented in this thesis will be useful in the continuing search for novel bioactive compounds, the diagnosis of fungal infections, and as a source of insight into the interactions between microorganisms. Moreover, they show that even extensively studied fungal genera such as Aspergillus and Penicillium are not completely understood and may produce unexpected or previously unknown bioactive metabolites under appropriate conditions.

    List of papers
    1. Antimicrobial activity of filamentous fungi isolated from highly antibiotic-contaminated river sediment
    Open this publication in new window or tab >>Antimicrobial activity of filamentous fungi isolated from highly antibiotic-contaminated river sediment
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    2012 (English)In: Infection ecology & epidemiology, ISSN 2000-8686, Vol. 2, p. 11591-Article in journal (Refereed) Published
    Abstract [en]

    Background:

    Filamentous fungi are well known for their production of substances with antimicrobial activities, several of which have formed the basis for the development of new clinically important antimicrobial agents. Recently, environments polluted with extraordinarily high levels of antibiotics have been documented, leading to strong selection pressure on local sentinel bacterial communities. In such microbial ecosystems, where multidrug-resistant bacteria are likely to thrive, it is possible that certain fungal antibiotics have become less efficient, thus encouraging alternative strategies for fungi to compete with bacteria.

    Methods:

    In this study, sediment of a highly antibiotic-contaminated Indian river was sampled in order to investigate the presence of cultivable filamentous fungi and their ability to produce substances with antimicrobial activity.

    Results:

    Sixty one strains of filamentous fungi, predominantly various Aspergillus spp. were identified. The majority of the Aspergillus strains displayed antimicrobial activity against methicillin-resistant Staphylococcus aureus, extended-spectrum beta-lactamase-producing Escherichia coli, vancomycin-resistant Enterococcus faecalis and Candida albicans. Bioassay-guided isolation of the secondary metabolites of A. fumigatus led to the identification of gliotoxin.

    Conclusion:

    This study demonstrated proof of principle of using bioassay-guided isolation for finding bioactive molecules

    Keywords
    secondary metabolites, Aspergillus, gliotoxin
    National Category
    Microbiology
    Research subject
    Pharmacognosy
    Identifiers
    urn:nbn:se:uu:diva-188192 (URN)10.3402/iee.v2i0.11591 (DOI)
    Funder
    Vinnova
    Available from: 2012-12-13 Created: 2012-12-13 Last updated: 2015-03-11Bibliographically approved
    2. Penicillium nalgiovense Laxa isolated from Antarctica is a new source of the antifungal metabolite amphotericin B
    Open this publication in new window or tab >>Penicillium nalgiovense Laxa isolated from Antarctica is a new source of the antifungal metabolite amphotericin B
    Show others...
    2015 (English)In: Fungal biology and biothechnology, Vol. 2, no 1Article in journal (Refereed) Published
    Abstract [en]

    Background: The need for new antibiotic drugs increases as pathogenic microorganisms continue to develop resistance against current antibiotics. We obtained samples from Antarctica as part of a search for new antimicrobial metabolites derived from filamentous fungi. This terrestrial environment in the South Pole is hostile and extreme due to a sparsely populated food web, low temperatures, and insufficient liquid water availability. We hypothesize that this environment could cause the development of fungal defense or survival mechanisms not found elsewhere.

    Results: We isolated a strain of Penicillium nalgiovense Laxa from a soil sample obtained from an abandoned penguin’s nest. Amphotericin B was the only metabolite secreted from P. nalgiovense Laxa with noticeable antimicrobial activity,with minimum inhibitory concentration of 0.125 µg/mL against Candida albicans. This is the first time that amphotericin B has been isolated from an organism other than the bacterium Streptomyces nodosus. In terms of amphotericin B production, cultures on solid medium proved to be a more reliable and favorable choice compared to a liquid.

    Conclusions: These results encourage further investigation of the many unexplored sampling sites characterized by extreme conditions, and confirm filamentous fungi as potential sources of metabolites with antimicrobial activity.

    Keywords
    Amphotericin B, Penicillium nalgiovense Laxa, Antarctica
    National Category
    Medicinal Chemistry
    Research subject
    Pharmacognosy
    Identifiers
    urn:nbn:se:uu:diva-242609 (URN)10.1186/s40694-014-0011-x (DOI)
    Available from: 2015-01-28 Created: 2015-01-28 Last updated: 2018-01-11Bibliographically approved
    3. Induction of Gliotoxin Secretion in Aspergillus fumigatus by Bacteria-Associated Molecules
    Open this publication in new window or tab >>Induction of Gliotoxin Secretion in Aspergillus fumigatus by Bacteria-Associated Molecules
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    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e93685-Article in journal (Refereed) Published
    Abstract [en]

    Aspergillus fumigatus is the most common causative agent of mold diseases in humans, giving rise to life-threatening infections in immunocompromised individuals. One of its secreted metabolites is gliotoxin, a toxic antimicrobial agent. The aim of this study was to determine whether the presence of pathogen-associated molecular patterns in broth cultures of A. fumigatus could induce gliotoxin production. Gliotoxin levels were analyzed by ultra-performance liquid chromatography and mass spectrometry. The presence of a bacteria-derived lipopolysaccharide, peptidoglycan, or lipoteichoic acid in the growth media at a concentration of 5 mu g/ml increased the gliotoxin concentration in the media by 37%, 65%, and 35%, respectively. The findings reveal a correlation between the concentrations of pathogen-associated molecular patterns and gliotoxin secretion. This shows that there is a yet uncharacterized detection system for such compounds within fungi. Inducing secondary metabolite production by such means in fungi is potentially relevant for drug discovery research. Our results also give a possible explanation for the increased virulence of A. fumigatus during bacterial co-infection, one that is important for the transition from colonization to invasiveness in this pulmonary disease.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-224740 (URN)10.1371/journal.pone.0093685 (DOI)000334107500056 ()
    Available from: 2014-05-21 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved
    4. Bis(methyl)gliotoxin and gliotoxin in bronchoalveolar lavage fluids are not suitable markers for invasive aspergillosis
    Open this publication in new window or tab >>Bis(methyl)gliotoxin and gliotoxin in bronchoalveolar lavage fluids are not suitable markers for invasive aspergillosis
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Invasive aspergillosis is challenging to diagnose partly due to shortcomings in sensitivity, reliability, and selectivity of current diagnostic methods, which rely on cultures, assays, and histopathology. This problem may be addressed by chemical analysis of metabolites in lung fluid from infected patients. Gliotoxin and bis(methyl)gliotoxin have been pinpointed as potential marker metabolites in serum and plasma for invasive aspergillosis patients, but whether lung fluid samples could be assessed for these markers is still unknown.

    Methods: Bronchoalveolar lavage samples were taken from 42 individuals with a variety of pulmonary diseases whereof  20 were diagnosed with possible invasive aspergillosis. The samples were analyzed with ultra high performance liquid chromatography coupled to triple quadropole time-of-flight mass spectrometry to investigate the use of the Aspergillus fumigatus metabolites gliotoxin and bis(methyl)gliotoxin as marker metabolites for invasive aspergillosis.

    Results: Gliotoxin was not detected in any of the 42 samples, but  bis(methyl)gliotoxin in 10 (24%). Bis(methyl)gliotoxin was detected in 5 (25%) of the 20 patients with possible IA and in 5 (23%) in the other 22 samples. One unknown compound (357.30 m/z) with a similar mass spectrum profile to bis(methyl)gliotoxin (357.09 m/z) was found in 32 (76%) of all samples.

    Conclusions: Neither gliotoxin nor bis(methyl)gliotoxin appears to be an acceptable marker metabolite in bronchoalveolar lavage fluids for invasive aspergillosis. Further development of MS-based analyses should include chromatography. 

    Keywords
    Invasive aspergillosis, gliotoxin, bis(methyl)gliotoxin, Aspergillus fumigatus, diagnosis
    National Category
    Medicinal Chemistry
    Research subject
    Pharmacognosy
    Identifiers
    urn:nbn:se:uu:diva-242610 (URN)
    Available from: 2015-01-28 Created: 2015-01-28 Last updated: 2018-01-11Bibliographically approved
  • 305.
    Svahn, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala Universitet.
    Chryssanthou, Erja
    Olsen, Björn
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Penicillium nalgiovense Laxa isolated from Antarctica is a new source of the antifungal metabolite amphotericin B2015In: Fungal biology and biothechnology, Vol. 2, no 1Article in journal (Refereed)
    Abstract [en]

    Background: The need for new antibiotic drugs increases as pathogenic microorganisms continue to develop resistance against current antibiotics. We obtained samples from Antarctica as part of a search for new antimicrobial metabolites derived from filamentous fungi. This terrestrial environment in the South Pole is hostile and extreme due to a sparsely populated food web, low temperatures, and insufficient liquid water availability. We hypothesize that this environment could cause the development of fungal defense or survival mechanisms not found elsewhere.

    Results: We isolated a strain of Penicillium nalgiovense Laxa from a soil sample obtained from an abandoned penguin’s nest. Amphotericin B was the only metabolite secreted from P. nalgiovense Laxa with noticeable antimicrobial activity,with minimum inhibitory concentration of 0.125 µg/mL against Candida albicans. This is the first time that amphotericin B has been isolated from an organism other than the bacterium Streptomyces nodosus. In terms of amphotericin B production, cultures on solid medium proved to be a more reliable and favorable choice compared to a liquid.

    Conclusions: These results encourage further investigation of the many unexplored sampling sites characterized by extreme conditions, and confirm filamentous fungi as potential sources of metabolites with antimicrobial activity.

  • 306.
    Svahn, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chryssanthou, Erja
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Bis(methyl)gliotoxin and gliotoxin in bronchoalveolar lavage fluids are not suitable markers for invasive aspergillosisManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Invasive aspergillosis is challenging to diagnose partly due to shortcomings in sensitivity, reliability, and selectivity of current diagnostic methods, which rely on cultures, assays, and histopathology. This problem may be addressed by chemical analysis of metabolites in lung fluid from infected patients. Gliotoxin and bis(methyl)gliotoxin have been pinpointed as potential marker metabolites in serum and plasma for invasive aspergillosis patients, but whether lung fluid samples could be assessed for these markers is still unknown.

    Methods: Bronchoalveolar lavage samples were taken from 42 individuals with a variety of pulmonary diseases whereof  20 were diagnosed with possible invasive aspergillosis. The samples were analyzed with ultra high performance liquid chromatography coupled to triple quadropole time-of-flight mass spectrometry to investigate the use of the Aspergillus fumigatus metabolites gliotoxin and bis(methyl)gliotoxin as marker metabolites for invasive aspergillosis.

    Results: Gliotoxin was not detected in any of the 42 samples, but  bis(methyl)gliotoxin in 10 (24%). Bis(methyl)gliotoxin was detected in 5 (25%) of the 20 patients with possible IA and in 5 (23%) in the other 22 samples. One unknown compound (357.30 m/z) with a similar mass spectrum profile to bis(methyl)gliotoxin (357.09 m/z) was found in 32 (76%) of all samples.

    Conclusions: Neither gliotoxin nor bis(methyl)gliotoxin appears to be an acceptable marker metabolite in bronchoalveolar lavage fluids for invasive aspergillosis. Further development of MS-based analyses should include chromatography. 

  • 307.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Methods in Medicinal Chemistry: Mechanistic Investigations and Virtual Screening Development2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis.

    In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally.

    The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods.

    Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind.

    Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

    List of papers
    1. Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
    Open this publication in new window or tab >>Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
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    2013 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, no 2, p. 490-497Article in journal (Refereed) Published
    Abstract [en]

    The reaction mechanism of palladium(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system.

    National Category
    Medical and Health Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-196041 (URN)10.1021/om3009525 (DOI)000314332100017 ()
    Available from: 2013-03-04 Created: 2013-03-04 Last updated: 2017-12-06Bibliographically approved
    2. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Open this publication in new window or tab >>Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
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    2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 41, p. 13803-13810Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

    Keywords
    decarboxylation, density functional calculations, mass spectrometry, microwave chemistry, palladium
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-210180 (URN)10.1002/chem.201301809 (DOI)000325135800026 ()
    Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-12-06Bibliographically approved
    3. Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
    Open this publication in new window or tab >>Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    palladium, DFT, mechanism, styrene
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259441 (URN)
    Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2015-10-01
    4. Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    Open this publication in new window or tab >>Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    2012 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, no 1, p. 225-232Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169381 (URN)10.1021/ci2004835 (DOI)000299351600021 ()
    Available from: 2012-02-28 Created: 2012-02-28 Last updated: 2018-01-12Bibliographically approved
    5. Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Open this publication in new window or tab >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
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    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Structural Biology Pharmaceutical Chemistry
    Research subject
    Chemistry with specialization in Bioorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
    Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2018-03-05Bibliographically approved
    6. Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
    Open this publication in new window or tab >>Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
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    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, no 9, p. 1984-1993Article in journal (Refereed) Published
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259442 (URN)10.1021/acs.jcim.5b00359 (DOI)000362056900018 ()26252078 (PubMedID)
    Funder
    Carl Tryggers foundation Swedish Research Council
    Available from: 2015-08-05 Created: 2015-08-04 Last updated: 2018-01-11Bibliographically approved
  • 308.
    Svensson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundbäck, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates2015In: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, no 9, p. 1984-1993Article in journal (Refereed)
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

  • 309.
    Svensson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods2012In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, no 1, p. 225-232Article in journal (Refereed)
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

  • 310.
    Svensson, Lars A.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Chiral packed capillary chromatography using an in-column immobilized selector: With special emphasis on vancomycin1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Packed fused silica capillary columns have been used for enantioseparation of drugs and related compounds. The technique to prepare the chiral stationary phase (CSP) involved a reductive amination of aldehyde functionalized silica with a chiral selector. The immobilization was performed in the packed column, thereby minimizing the use of selector. An α-chymotrypsin CSP was used to investigate the influence of the pore size on the chromatographic performance. Both selectivity and efficiency were better on a 1000 Å pore size material.

    The retention mechanism of some arylpropionic acids on a vancomycin CSP was studied. A two-site retention model was sufficient to qualitatively describe the effects of different mobile phase compositions, including buffer, modifier and counter ion concentration as well as pH. A closer investigation of the immobilization reaction was also conducted for the vancomycin selector with the aim of elucidating if the linkage to the silica affected the enantioselective retention. To accomplish this one of the two amino groups was temporarily protected while the other was linked to the silica. However, no significant difference in enantioresolution between the two defined CSPs formed was obtained in comparison with the one resulting from the immobilization of native vancomycin.

    Different types of interactions seemed to be important in different modes of chromatography. Reversed phase LC primarily separated acidic compounds while polar organic phase LC (POPLC) was better suited to resolve basic compounds. Supercritical fluid chromatography (SFC) and normal phase LC could separate both acidic and basic as well as neutral compounds, but SFC had superior chromatographic performance resulting in both higher efficiency and selectivity.

    Acid and base interactions between analyte and selector seems to be the key process for chiral discrimination. It has previously been shown that the N-terminal of vancomycin was important for acidic compounds. With the use of an analogous selector, ristocetin A, it is here indicated that the C-terminal is equally important for resolution of bases.

  • 311. Syvänen, Stina
    et al.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Organic Chemistry.
    Genchel, Tove
    Lindhe, Örjan
    Antoni, Gunnar
    Långström, Bengt
    [1-11C]Ethyl iodide and [1-11C]propyl iodide in the synthesis of two potential NK1-receptor ligands and initial PET-imagingManuscript (Other academic)
  • 312.
    Szałaj, Natalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lu, Lu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.
    Benediktsdottir, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Zamaratski, Edouard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Cao, Sha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olanders, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hedgecock, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mowbray, Sherry L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase.2018In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, p. 1346-1360Article in journal (Refereed)
    Abstract [en]

    Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

  • 313.
    Sänger-van de Griend, Cari Elise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Enantiomeric separations by capillary electrophoresis in pharmaceutical analysis1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The chiral capillary electrophoresis mechanism is studied by evaluating the enantiomeric separations of a series of local anaesthetic analogues, the sixteen different optical isomers of a tetrapeptide and a series of glycyl, alanyl and leucyl dipeptides. The usefulness of mobility difference plots is appraised and important method parameters, such as the selection of the chiral selector, the chiral selector concentration, the chiral selector purity, the pH and the composition of the electrophoresis solution, are identified and discussed, bearing method robustness in mind. The evaluation of the mobility difference plots obtained for the eight enantiomer pairs of the tetrapeptide resulted in an extension of the mobility difference model. In the extended model the formation of enantiomer-chiral selector complexes with a stoichiometry higher than 1:1 is taken into account. With this model it is demonstrated that complex formation of one tetrapeptide molecule with more than one cyclodextrin molecule is a possible explanation for the experimentally obtained data.

    Cyclodextrins were evaluated as chiral selectors for dipeptides and have been shown to be applicable to the enantiomeric separation of aromatic and non-polar aliphatic dipeptides. By developing and validating an enantiomeric purity determination method for ropivacaine substance and products, it is shown that chiral capillary electrophoresis is a feasible technique for pharmaceutical analysis, which can offer an alternative and/or complement to chiral liquid chromatography.

  • 314.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-Catalyzed Carbonylation and Arylation Reactions2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium-catalyzed reactions have found widespread use in contemporary organic chemistry due to their impressive range of functional group tolerance and high chemo- and regioselectivity. The pioneering contributions to the development of the Pd-catalyzed C-C bond forming cross-coupling reaction were rewarded with the Nobel Prize in Chemistry in 2010. Today, this is a rapidly growing field, and the development of novel methods, as well as the theoretical understanding of the various processes involved are of immense importance for continued progress in this field.

    The aim of the work presented in this thesis was to develop novel palladium(0)- and palladium(II)-catalyzed reactions. The work involved in achieving this aim led to the development of a Mo(CO)6-mediated carbonylative Stille cross coupling reaction for the preparation of various deoxybenzoins. The protocol utilized convenient gas-free conditions to facilitate the carbonylative coupling of benzyl bromides and chlorides with aryl and heteroaryl stannanes. Mo(CO)6-assisted conditions were then used in the development of a general protocol suitable for the aminocarbonylation of aryl triflates. Both electron-poor and electron-rich triflates were coupled with primary, secondary and aryl amines. In addition, DMAP was found to be a beneficial additive when using sterically hindered or poorly nucleophilic amines.

    An efficient and convenient method for the synthesis of styrenes from arylboranes was developed, employing the relatively inexpensive vinyl acetate as the ethene source under Pd(II)-catalyzed conditions. The reaction mechanism was studied using ESI-MS, and a plausible catalytic cycle was proposed.

    A method for the oxidative Heck reaction employing aryltrifluoroborates and aryl MIDA boronates was also developed. Electron-rich and electron-poor olefins were regioselectively arylated under microwave-assisted conditions. Various arylboron species were identified in an ongoing reaction using ESI-MS.   

    Further investigations led to the development of a direct method for the synthesis of arylamidines from aryltrifluoroborates and cyanamides. Under Pd(II)-catalyzed conditions it was possible to insert the aryl into primary, secondary and tertiary cyanamides.

    Finally, a desulfitative method for the synthesis of aryl ketones was developed. A variety of aryl sulfinates were effectively inserted into alkyl- and aryl nitriles. The mechanism was further investigated using ESI-MS and a plausible catalytic cycle was proposed.

    List of papers
    1. Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl
    Open this publication in new window or tab >>Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl
    2010 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 52, p. 6886-6889Article in journal (Refereed) Published
    Abstract [en]

    Stille-type carbonylative cross-couplings, employing palladium catalysis and Mo(CO)6 as the carbon monoxide carrier, were used for the preparation of deoxybenzoins. Straightforward transformations were conveniently performed in closed vessels at 100 C, providing the products in good yields. Benzyl bromides and chlorides were used as coupling partners with aryl and heteroaryl stannanes. This mild three-component carbonylation employs the destabilizing agent DBU to promote smooth release of carbon monoxide from Mo(CO)6, which made this protocol operationally simple and minimized the formation of Stille diarylmethane products.

    Keywords
    Stille, molybdenum hexacarbonyl, deoxybenzoins, palladium
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-167715 (URN)10.1016/j.tetlet.2010.10.115 (DOI)000285670400023 ()
    Available from: 2012-01-31 Created: 2012-01-31 Last updated: 2017-12-08Bibliographically approved
    2. Microwave-promoted aminocarbonylation of aryl triflates using Mo(CO)(6) as a solid CO source
    Open this publication in new window or tab >>Microwave-promoted aminocarbonylation of aryl triflates using Mo(CO)(6) as a solid CO source
    2008 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 42, p. 6115-6118Article in journal (Refereed) Published
    Abstract [en]

    Palladium-catalyzed carbonylations of aryl triflates with a range of nucleophiles using Mo(CO)(6) as a solid CO source were explored. The reactions proceeded smoothly providing moderate to good yields of the corresponding aryl amides, esters, or acylsulfonamides after only 20 min of microwave irradiation. The acyl transfer reagent 4-dimethylaminopyridine was found to promote some of the more difficult transformations. (C) 2008 Elsevier Ltd. All rights reserved.

    Keywords
    carbonylation, microwave, palladium, aryl triflate, DMAP
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-104379 (URN)10.1016/j.tetlet.2008.08.014 (DOI)000259883800024 ()0040-4039 (ISBN)
    Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
    3. Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Open this publication in new window or tab >>Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Show others...
    2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 18, p. 4630-4636Article in journal (Refereed) Published
    Abstract [en]

    Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less than 30 min at 140 degrees C in the absence of base and tolerates a variety of substituents. No palladium reoxidant is needed and the vinylation is performed under non-inert conditions. Mass spectrometry (electrospray ionization mass spectrometry (ESIMS) and tandem mass spectrometry   (MS/MS)) was used to identify cationic palladium-containing complexes in ongoing reactions. The key intermediates that have been detected, together with experiments that used deuterated vinyl acetate, support the existence of catalytically active palladium hydride species, and that it is the arylation of ethylene, not vinyl acetate, which   generates the styrene product. The mechanism of the reaction is discussed in terms of the palladium(II) intermediates mentioned above.

    Keywords
    Heck reaction, mass spectrometry, mechanistic studies, palladium, styrene
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102918 (URN)10.1002/chem.200802744 (DOI)000265955200018 ()19274694 (PubMedID)
    Available from: 2009-05-13 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
    4. Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl N-Methyliminodiacetic Acid (MIDA) Boronates
    Open this publication in new window or tab >>Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl N-Methyliminodiacetic Acid (MIDA) Boronates
    Show others...
    2012 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 1, no 3, p. 140-146Article in journal (Refereed) Published
    Place, publisher, year, edition, pages
    Weinheim: Wiley-VCH Verlagsgesellschaft, 2012
    Keywords
    Heck reactions, N-methyliminodiacetic acid (MIDA), oxidative reactions, palladium complexes, trifluoroborate
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-167718 (URN)10.1002/open.201200007 (DOI)000328607400004 ()
    Funder
    Swedish Research Council
    Available from: 2012-01-31 Created: 2012-01-31 Last updated: 2017-12-08Bibliographically approved
    5. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
    Open this publication in new window or tab >>Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
    Show others...
    2012 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, no 9, p. 2394-2397Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-167719 (URN)10.1021/ol300813c (DOI)000303492200052 ()
    Available from: 2012-01-31 Created: 2012-01-31 Last updated: 2017-12-08Bibliographically approved
    6. Microwave-Assisted Palladium(II)-Catalyzed Synthesis of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof
    Open this publication in new window or tab >>Microwave-Assisted Palladium(II)-Catalyzed Synthesis of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof
    2011 (English)In: ACS Catalysis, ISSN 2155-5435, Vol. 1, no 11, p. 1455-1459Article in journal (Refereed) Published
    Abstract [en]

    A fast palladium(II)-catalyzed and microwave-promoted procedure using 6-methyl-2,2'-bipyridyl as ligand to synthesize aryl ketones from aryl sulfinates and nitriles is described. More importantly, the first detailed investigation of the reaction mechanism using direct ESI-MS studies is reported.

    Keywords
    palladium, catalysis, desulfination, aryl sulfinates, aryl ketones, nitriles, ESI-MS, microwave
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-162466 (URN)10.1021/cs200428u (DOI)000296598000002 ()
    Available from: 2011-11-30 Created: 2011-11-30 Last updated: 2012-06-01Bibliographically approved
  • 315.
    Talibov, Vladimir O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Linkuvienė, Vaida
    Matulis, Daumantas
    Danielson, Helena U.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Kinetically Selective Inhibitors of Human Carbonic Anhydrase Isozymes I, II, VII, IX, XII, and XIII2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, p. 2083-2093Article in journal (Refereed)
    Abstract [en]

    To get a better understanding of the possibility of developing selective carbonic anhydrase (CA) inhibitors, interactions between 17 benzenesulphonamide ligands and 6 human CAs (full-length CA I, II, VII, and XIII and catalytic domains of CA IX and XII) were characterized using surface plasmon resonance and fluorescent-based thermal shift assays. Kinetics revealed that the strongest binders had subnanomolar affinities with low dissociation rates (i.e., kd values around 1 × 10(-3) s(-1)) or were essentially irreversible. Chemodynamic analysis of the interactions highlighted an intrinsic mechanism of the CA-sulphonamide interaction kinetics and showed that slow dissociation rates were mediated by large hydrophobic contacts. The studied inhibitors demonstrated a high cross-reactivity within the protein family. However, according to chemical phylogenetic analysis developed for kinetic data, several ligands were found to be selective against certain CA isozymes, indicating that it should be possible to develop selective CA inhibitors suitable for clinical use.

  • 316.
    Tevell Åberg, Annica
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Detection and Structure Elucidation of Drug Metabolites in Biological Samples using HPLC-MS/MS Techniques2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the structure elucidation of drug metabolites in biological samples by the use of high performance liquid chromatography (HPLC) atmospheric pressure ionization (API) tandem mass spectrometry (MS/MS). Due to their different advantages, various mass analyzers have been used in the different experiments.

    The metabolism of clemastine, flutamide, and meloxicam were studied in vitro and/or in vivo in different species such as humans, dogs, and horses. Accurate mass measurements with the quadrupole-time of flight mass spectrometer and MSn data supplied by the ion trap instrument were useful in the structural investigation of the product ions of the drugs and their metabolites. Different scan modes of the triple quadrupole mass spectrometer resulted in great flexibility, selectivity, and sensitivity in the qualitative and semi-quantitative studies. Additionally, hydrogen/deuterium exchange and experiments with atmospheric pressure chemical ionization were conducted, and the fungus Cunninghamella elegans was utilized to produce amounts of drug metabolites sufficient for structural investigation.

    Six isomers of oxidized clemastine were detected and characterized in C. elegans incubations and their retention times and mass spectral data were compared to the metabolites detected in urine samples. Two of the metabolites were concluded to be diastereomeric N-oxides.

    In urine from horses treated with meloxicam, the peak of 5'-hydroxymethylmeloxicam resulted in much higher intensity than the parent drug or the other metabolites, and it was detectable for at least 14 days after the last dose in some of the horses. That is useful information in the development of analytical methods for the detection of prohibited use of meloxicam.

    A mercapturic acid conjugate of hydroxyflutamide was detected in urine from cancer patients, which indicated that a reactive metabolite was formed. This metabolite could be responsible for the adverse events reported for flutamide.

    The results from the four papers included in the thesis clearly demonstrate the usefulness and the flexibility of the HPLC-API-MS/MS technique.

    List of papers
    1. Identification of some new clemastine metabolites in dog, horse, and human urine with liquid chromatography/tandem mass spectrometry.
    Open this publication in new window or tab >>Identification of some new clemastine metabolites in dog, horse, and human urine with liquid chromatography/tandem mass spectrometry.
    2004 (English)In: Rapid Commun Mass Spectrom, ISSN 0951-4198, Vol. 18, no 19, p. 2267-72Article in journal (Other scientific) Published
    Identifiers
    urn:nbn:se:uu:diva-67268 (URN)15384147 (PubMedID)
    Available from: 2004-11-11 Created: 2004-11-11 Last updated: 2011-01-12
    2. Structure elucidation of N-oxidized clemastine metabolites by HPLC-MS-MS and the use of Cunninghamella elegans to facilitate drug metabolite identification
    Open this publication in new window or tab >>Structure elucidation of N-oxidized clemastine metabolites by HPLC-MS-MS and the use of Cunninghamella elegans to facilitate drug metabolite identification
    (English)Manuscript (Other (popular science, discussion, etc.))
    Keywords
    HPLC-MS/MS, hydrogen/deuterium exchange, N-oxidation, Clemastine, metabolites
    Identifiers
    urn:nbn:se:uu:diva-98343 (URN)
    Available from: 2009-02-19 Created: 2009-02-19 Last updated: 2010-01-14
    3. Flutamide metabolism in four different species in vitro and identification of flutamide metabolites in human patient urine by high performance liquid chromatography/tandem mass spectrometry.
    Open this publication in new window or tab >>Flutamide metabolism in four different species in vitro and identification of flutamide metabolites in human patient urine by high performance liquid chromatography/tandem mass spectrometry.
    Show others...
    2006 (English)In: Drug Metab Dispos, ISSN 0090-9556, Vol. 34, no 6, p. 984-92Article in journal (Refereed) Published
    Keywords
    Androgen Antagonists/*metabolism/therapeutic use/urine, Animals, Antineoplastic Agents; Hormonal/*metabolism/therapeutic use/urine, Biotransformation, Chromatography; Liquid, Comparative Study, Dogs, Flutamide/*analogs & derivatives/*metabolism/standards/therapeutic use/urine, Glucuronidase, Humans, In Vitro, Male, Microsomes; Liver/metabolism, Prostate/metabolism, Prostatic Neoplasms/drug therapy/*metabolism/urine, Rats, Spectrometry; Mass; Electrospray Ionization, Swine
    Identifiers
    urn:nbn:se:uu:diva-80893 (URN)16540588 (PubMedID)
    Available from: 2007-03-03 Created: 2007-03-03 Last updated: 2011-01-11
    4. A mass spectromeric study on meloxicam metabolism in horses and the fungus Cunninghamella elegans, and the relevance of this microbial system as a model of drug metabolism in the horse
    Open this publication in new window or tab >>A mass spectromeric study on meloxicam metabolism in horses and the fungus Cunninghamella elegans, and the relevance of this microbial system as a model of drug metabolism in the horse
    2009 (English)In: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 44, no 7, p. 1026-1037Article in journal (Refereed) Published
    Abstract [en]

    This paper describes a study where the metabolism of the non-steroidal   anti-inflammatory drug meloxicam was investigated in six horses and in  the filamentous fungus Cunninghamella elegans. The metabolites identified were compared between the species, and then the fungus was  used to produce larger amounts of the metabolites for future use as   reference material. C. elegans proved to be a good model of phase I   meloxicam metabolism in horses since all four metabolites found were   the same in both species. Apart from the two main metabolites,   5'-hydroxymethylmeloxicam and 5'-carboxymeloxicam, a second isomer of   hydroxymeloxicam and dihydroxylated meloxicam were detected for the   first time in horse urine and the microbial incubations. Phase II   metabolites were not discovered in the C. elegans samples but   hydroxymeloxicam glucuronide was detected intact in horse urine for the   first time in this study. Urine from six horses was further analyzed in   a semi-quantitative sense and 5'-hydroxymethylmeloxicam gave peaks with   much higher intensity compared to the parent drug and the other   metabolites, and was detected for at least 14 days after the last given   dose in some of the horses. From the results presented in this article,   we suggest that analytical methods developed for the detection of   meloxicam in horse urine after prohibited use should focus on the   5'-hydroxymethyl metabolite and that C. elegans can be used to produce  large amounts of this metabolite for potential future use as a reference compound.

    Keywords
    Meloxicam, metabolism, mass spectrometry, horse, Cunninghamella elegans
    National Category
    Pharmaceutical Sciences
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-98287 (URN)10.1002/jms.1575 (DOI)000268505500003 ()
    Available from: 2009-02-19 Created: 2009-02-18 Last updated: 2018-01-13Bibliographically approved
  • 317.
    Thorsteinsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Separation of peptides by capillary electrophoresis: Application of chemometrics for evaluation of separation performance in micellar electrokinetic chromatography1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The separation of enkephalin-related peptides and protein kinase A peptide substrates werestudied in micellar electrokinetic chromatography and compared with capillary zoneelectrophoresis. Special interest was focused on systems where the electroosmosis wasreversed in combination with neutral micellar agents. Such systems involve the unique combination of minimizing surface interactions by electrostatic effects and increasing themigration time window. This was accomplished either by addition of cationic monomericamines to the background electrolyte or by using fused silica capillaries modified byimmobilizing an amine to the surface.

    The selectivities were enhanced by adding anionic taurodeoxycholate micelles to the BGE.The efficiencies obtained were highly dependent on the extent of distribution of the peptides tothe micellar phase. The effect of experimental factors that cause band broadening duringseparation were evaluated by fractional factorial design and response surface modelling. Partialleast square (PLS) regression analysis revealed that very high efficiencies were obtained forpeptides with low distribution to the micelles, while the efficiencies drastically decreased forpeptides strongly associated to the micelles, probably due to slow sorption-desorption kinetics.

    The separation of enkephalin-related peptides in a system with anionic sodium dodecylmicelles (SDS) was optimized by utilizing experimental design and response surfacemodelling. Such strategies have the advantages of greatly reducing the number of experimentsand allowing identification of interaction effects between the variables. The effect ofacetonitrile was studied, in four different concentration domains, together with SDSconcentration, temperature and the ionic strength of the buffer via central composite design,and related to resolution, migration factor and migration time window utilizing PLS-regression. The results revealed a complex system with very different influences of theexperimental variables in respective domain. The effect of acetonitrile is highly non-linear insystems of this kind and dependent on the temperature used. A change in the thermodynamicsof the distribution behaviour was observed at increasing acetonitrile concentrations. Further,the relationships between different parameters that influence the resolution were investigatedby principal component analysis.

  • 318.
    Torstensson, Richard
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Functional regulation of the dopaminergic system in vivo: Experimental and clinical studies with positron emission tomography1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Positron emission tomography (PET) is a non-invasive imaging technique used to quantitate the kinetics of a radiotracer in such physiological processes as receptor binding and enzyme activity. Radiolabelled L-DOPA has previously been used as a tracer for the dopaminergic system. The focus of the present study was to investigate the validity and feasibility of the 11C-labelled L-DOPA to measure aromatic amino acid decarboxylase (AADC) activity as an indicator of the functional tone of the presynaptic dopaminergic system in vivo. The regulation of the presynaptic dopaminergic system was studied in rhesus monkeys, as well as in humans in the healthy and diseased states.

    The intra- and inter-individual variations of the striatal influx rate constant for L-[β-11C]DOPA, i.e. Ki, measured with PET were found to be 10 and 15% between days, respectively. Furthermore, in rhesus monkeys, the Ki value was shown to decrease slightly (1 to 2% per year) as a function of time. Radiolabelled L-DOPA and its 6-fluoroanalogue were compared as PET tracers. Differences in the peripheral metabolism of L-DOPA and the fluorinated analogue were confirmed. The modulating effects of 6R-BH4 on L-[β-11C]DOPA Ki were only found for the L-6-fluorodopa tracer when animals had been pretreated with a COMT inhibitor.

    Pharmacological treatments induced changes in the L-[β-11C]DOPA Ki. The dopamine receptor agonist, apomorphine, decreased the striatal Ki value and L-DOPA as well as 6R-BH4, a co-factor for tyrosine hydroxylase, increased the Ki values. Moreover, the effects of these drugs on the striatal Ki value showed significant baseline dopaminergic state-dependent effects. The regulating effect on the L-[β-11C]DOPA Ki induced by different pharmacological treatments was shown to correlate with changes in AADC activity measured in rat brain homogenates.

    An intriguing new compound, (-)-OSU6162, was investigated with respect to its functional effects in the regulation of the presynaptic dopaminergic system. The compound induced a normalising effect on striatal L-[β-11C]DOPA Ki values, i.e. (-)-OSU6162 increased the striatal Ki value in monkeys with initial low values and decreased the Ki values in monkeys with initial high values.

    In patients with Parkinson's disease (PD), marked differences in the functional regulation of the presynaptic dopaminergic tone were found in patients with early and advanced disease. After therapeutic levodopa infusions, patients with advanced PD showed an increase in striatal L-[β-11C]DOPA Ki values; in patients with early PD, levodopa induced a decrease in striatal Ki values. A diminished presynaptic autoreceptor function in advanced PD was proposed and demonstrated in a clinical study using a therapeutic apomorphine challenge.

    In conclusion, the radiotracer L-[β-11C]DOPA was shown not only to measure the AADC integrity in the presynaptic dopaminergic system but also to reflect the functional tone of this neurotransmitter system in vivo.

  • 319.
    Ujan, Rabail
    et al.
    Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan.
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Channar, Pervaiz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Larik, Fayaz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Abbas, Qamar
    Univ Sindh, Dept Physiol, Jamshoro 76080, Pakistan.
    Alajmi, Mohamed F.
    King Saud Univ, Dept Pharmacognosy, Coll Pharm, Riyadh 11451, Saudi Arabia.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Rind, Mahboob Ali
    Univ Sindh, Dr MA Kazi Inst Chem, Jamshoro 76080, Pakistan.
    Hassan, Mubashir
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea.
    Raza, Hussain
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea.
    Seo, Sung-Yum
    Kongju Natl Univ, Coll Nat Sci, Dept Biol Sci, Gongju 314701, Chungnam, South Korea.
    Drug-1,3,4-Thiadiazole Conjugates as Novel Mixed-Type Inhibitors of Acetylcholinesterase: Synthesis, Molecular Docking, Pharmacokinetics, and ADMET Evaluation2019In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 5, article id 860Article in journal (Refereed)
    Abstract [en]

    A small library of new drug-1,3,4-thiazidazole hybrid compounds (3a-3i) was synthesized, characterized, and assessed for their acetyl cholinesterase enzyme (AChE) inhibitory and free radical scavenging activities. The newly synthesized derivatives showed promising activities against AChE, especially compound 3b (IC50 18.1 +/- 0.9 nM), which was the most promising molecule in the series, and was substantially more active than the reference drug (neostigmine methyl sulfate; IC50 2186.5 +/- 98.0 nM). Kinetic studies were performed to elucidate the mode of inhibition of the enzyme, and the compounds showed mixed-type mechanisms for inhibiting AChE. The Ki of 3b (0.0031 mu M) indicates that it can be very effective, even at low concentrations. Compounds 3a-3i all complied with Lipinski's Rule of Five, and showed high drug-likeness scores. The pharmacokinetic parameters revealed notable lead-like properties with insignificant liver and skin-penetrating effects. The structure-activity relationship (SAR) analysis indicated pi-pi interactions with key amino acid residues related to Tyr124, Trp286, and Tyr341.

  • 320. Valero-Esquitino, Verónica
    et al.
    Lucht, Kristin
    Namsolleck, Pawel
    Monnet-Tschudi, Florianne
    Stubbe, Tobias
    Lucht, Franziska
    Liu, Meng
    Ebner, Friederike
    Brandt, Christine
    Danyel, Leon A
    Villela, Daniel C
    Paulis, Ludovit
    Thoene-Reineke, Christa
    Dahlöf, Björn
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unger, Thomas
    Sumners, Colin
    Steckelings, U Muscha
    Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice2015In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 128, no 2, p. 95-109Article in journal (Refereed)
    Abstract [en]

    In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.

  • 321.
    Valitalo, Pyry
    et al.
    Leiden Univ, Div Pharmacol, Leiden, Netherlands..
    Kokki, Merja
    Kuopio Univ Hosp, Dept Anesthesia & Operat Serv, POB 100, FI-70029 Kuopio, Finland.;Univ Eastern Finland, Sch Med, Kuopio, Finland..
    Ranta, Veli-Pekka
    Univ Eastern Finland, Sch Pharm, Kuopio, Finland..
    Olkkola, Klaus T.
    Univ Helsinki, Dept Anesthesiol Intens Care & Pain Med, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kokki, Hannu
    Kuopio Univ Hosp, Dept Anesthesia & Operat Serv, POB 100, FI-70029 Kuopio, Finland.;Univ Eastern Finland, Sch Med, Kuopio, Finland..
    Maturation of Oxycodone Pharmacokinetics in Neonates and Infants: a Population Pharmacokinetic Model of Three Clinical Trials2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 5, p. 1125-1133Article in journal (Refereed)
    Abstract [en]

    Purpose The aim of the current population pharmacokinetic study was to quantify oxycodone pharmacokinetics in children ranging from preterm neonates to children up to 7 years of age. Methods Data on intravenous or intramuscular oxycodone administration were obtained from three previously published studies (n = 119). The median [range] postmenstrual age of the subjects was 299 days [170 days-7.8 years]. A population pharmacokinetic model was built using 781 measurements of oxycodone plasma concentration. The model was used to simulate repeated intravenous oxycodone administration in four representative infants covering the age range from an extremely preterm neonate to 1-year old infant. Results The rapid maturation of oxycodone clearance was best described with combined allometric scaling and maturation function. Central and peripheral volumes of distribution were nonlinearly related to bodyweight. The simulations on repeated intravenous administration in virtual patients indicated that oxycodone plasma concentration can be kept between 10 and 50 ng/ml with a high probability when the maintenance dose is calculated using the typical clearance and the dose interval is 4 h. Conclustions Oxycodone clearance matures rapidly after birth, and between-subject variability is pronounced in neonates. The pharmacokinetic model developed may be used to evaluate different multiple dosing regimens, but the safety of repeated doses should be ensured.

  • 322.
    Vallin, Karl S. A.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Regioselective Heck Coupling Reactions: Focus on Green Chemistry2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Carbon-carbon bond formation reactions are among the most important processes in chemistry, as they represent key steps in the synthesis of more complex molecules from simple precursors. This thesis describes mainly the development of novel regioselective applications of the mild and versatile palladium-catalyzed carbon-carbon coupling method, commonly known as the Heck reaction. In addition, this thesis will focus on environmentally friendly developments of the Heck reaction.

    Novel ligand-controlled internal Heck vinylations of vinyl ethers and enamides to form branched electron-rich dienes were performed with high regioselectivity. The vinylation of 2-hydroxyethyl vinyl ether permits a chemoselective transformation of a vinylic triflate or bromide into a blocked α,β-unsaturated methyl ketone. Furthermore, a simple separation of the palladium catalyst was achieved with new fluorous-tagged bidentate ligands in combination with fluorous solid phase extraction. The reaction times could be reduced up to 1000 times with controlled microwave heating in the palladium-catalyzed reactions with, in the majority of cases, retained, high selectivity.

    The development of a “green” regioselective arylation and vinylation method relying on an aqueous DMF-potassium carbonate system and excluding the toxic thallium salt has been accomplished. Ionic liquids as the versatile and environmentally friendly class of solvents have been used in rapid phosphine-free terminal Heck arylations with controlled microwave heating. Recycling of the catalytic medium was achieved after a simple product purification.

    List of papers
    1. Highly Selective Palladium-Catalyzed Synthesis of Protected a,ß-Unsaturated Methyl Ketones and 2-Alkoxy-1,3-Butadienes: High-Speed Chemistry by Microwave Flash Heating
    Open this publication in new window or tab >>Highly Selective Palladium-Catalyzed Synthesis of Protected a,ß-Unsaturated Methyl Ketones and 2-Alkoxy-1,3-Butadienes: High-Speed Chemistry by Microwave Flash Heating
    2000 (English)In: J. Org. Chem., Vol. 65, no 15, p. 4537-4542Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90267 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2013-07-04Bibliographically approved
    2. New Regioselective Heck-Vinylation with Enamides. Synthesis and Investigation of Fluorous Tagged Bidentate Ligands for Fast Separation
    Open this publication in new window or tab >>New Regioselective Heck-Vinylation with Enamides. Synthesis and Investigation of Fluorous Tagged Bidentate Ligands for Fast Separation
    Show others...
    (English)In: J. Org. Chem.Article in journal (Refereed) Submitted
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90268 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2013-07-04Bibliographically approved
    3. Aqueous DMF-Potassium Carbonate as a Substitute for Thallium and Silver Additives in the Palladium-Catalyzed Conversion of Aryl Bromides to Acetyl Arenes
    Open this publication in new window or tab >>Aqueous DMF-Potassium Carbonate as a Substitute for Thallium and Silver Additives in the Palladium-Catalyzed Conversion of Aryl Bromides to Acetyl Arenes
    2001 (English)In: J. Org. Chem., Vol. 66, no 12, p. 4340-4343Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90269 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2013-07-04Bibliographically approved
    4. High-Speed Heck Reactions in Ionic Liquid with Controlled Microwave Heating
    Open this publication in new window or tab >>High-Speed Heck Reactions in Ionic Liquid with Controlled Microwave Heating
    2002 (English)In: J. Org. Chem., Vol. 67, no 17, p. 6243-6246Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90270 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2013-07-04Bibliographically approved
  • 323.
    van Kuilenburg, André
    et al.
    Univ Amsterdam, Emma Childrens Hosp, Lab Genet Metabol Dis Pediat & Clin Genet, Dept Clin Chem,Acad Med Ctr, Amsterdam, Netherlands.
    Tarailo-Graovac, Maja
    Univ Calgary, Cumming Sch Med, Dept Biochem, Calgary, AB, Canada; Univ Calgary, Cumming Sch Med, Dept Mol Biol, Calgary, AB, Canada; Univ Calgary, Cumming Sch Med, Dept Med Genet, Calgary, AB, Canada; Univ Calgary, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada.
    Meijer, Judith
    Univ Amsterdam, Emma Childrens Hosp, Lab Genet Metabol Dis Pediat & Clin Genet, Dept Clin Chem,Acad Med Ctr, Amsterdam, Netherlands.
    Drogemoller, Britt
    Univ British Columbia, Ctr Mol Med & Therapeut, Dept Pediat, Vancouver, BC, Canada; Univ British Columbia, Ctr Mol Med & Therapeut, Dept Med Genet, Vancouver, BC, Canada.
    Vockley, Gerard
    Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA; Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA.
    Maurer, Dirk
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Dobritzsch, Doreen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Ross, Colin
    Univ British Columbia, Ctr Mol Med & Therapeut, Dept Pediat, Vancouver, BC, Canada; Univ British Columbia, Ctr Mol Med & Therapeut, Dept Med Genet, Vancouver, BC, Canada.
    Wasserman, Wyeth
    Univ British Columbia, Ctr Mol Med & Therapeut, Dept Pediat, Vancouver, BC, Canada; Univ British Columbia, Ctr Mol Med & Therapeut, Dept Med Genet, Vancouver, BC, Canada.
    Meinsma, Rutger
    Univ Amsterdam, Emma Childrens Hosp, Lab Genet Metabol Dis Pediat & Clin Genet, Dept Clin Chem,Acad Med Ctr, Amsterdam, Netherlands.
    Zoetekouw, Lida
    Univ Amsterdam, Emma Childrens Hosp, Lab Genet Metabol Dis Pediat & Clin Genet, Dept Clin Chem,Acad Med Ctr, Amsterdam, Netherlands.
    van Karnebeek, Clara
    Univ Amsterdam, Emma Childrens Hosp, Lab Genet Metabol Dis Pediat & Clin Genet, Dept Clin Chem,Acad Med Ctr, Amsterdam, Netherlands; Univ British Columbia, Ctr Mol Med & Therapeut, Dept Pediat, Vancouver, BC, Canada; Univ British Columbia, Ctr Mol Med & Therapeut, Dept Med Genet, Vancouver, BC, Canada.
    Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G > A and a large intragenic inversion in DPYD spanning intron 8 to intron 122018In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 7, p. 947-953Article in journal (Refereed)
    Abstract [en]

    Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with a variable clinical presentation. A family with three DPD-deficient patients presented with unusual clinical phenotypes including pregnancy-induced symptoms, transient visual impairment, severe developmental delay, cortical blindness, and delayed myelination in the brain. DPYD Sanger sequencing showed heterozygosity for the c.1905+1G>A mutation and a novel missense variant c.1700G>A (p.G567E). The recombinantly expressed p.G567E DPD variant showed increased temperature lability probably caused by structural rearrangements within the DPD protein. Genome sequencing of the affected son established compound heterozygosity for the c.1700G>A and an imperfect 115,731bp inversion with breakpoints at chr1: 98,113,121 (intron 8) and chr1: 97,997,390 (intron 12) of the DPYD associated with a 4bp deletion (chr1: 97,997,386_97,997,389del). Whole exome and mitochondrial DNA analyses for the mother and daughter did not reveal additional mutated genes of significance. Thus, an inversion in DPYD should be considered in patients with an inconclusive genotype or unusual clinical phenotype.

  • 324. Verbeek, Joost
    et al.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Huisman, Marc
    Schuit, Robert C
    Molthoff, Carla F M
    Voskuyl, Rob A
    de Lange, Elizabeth C
    Lammertsma, Adriaan A
    Windhorst, Albert D
    Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression.2018In: EJNMMI radiopharmacy and chemistry, ISSN 2365-421X, Vol. 3, article id 11Article in journal (Refereed)
    Abstract [en]

    Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.

    Results: [18F]2-(4-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]5) and [18F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]6) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [18F]5 and [18F]6 were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [18F]6 appeared to be metabolically unstable in vivo, while [18F]5 showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [18F]5 across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.

    Conclusion: In conclusion, [18F]5 and [18F]6 were successfully and reproducibly synthesized, albeit with low radiochemical yields. [18F]5 appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.

  • 325.
    Vikeved, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Drug discovery against leishmaniasis: Bio- and chemoinformatic guided strategies for target evaluation and hit identification2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Leishmaniasis is a neglected tropical disease mainly affecting poor people in developing countries. It is caused by infections of flagellated protozoa belonging to genus Leishmania. The few available drugs are associated with problems such as low effectiveness, severe side effects and resistance development. The overall aim of this thesis is to aid in drug discovery against leishmaniasis – primarily using bio- and chemoinformtic approaches.

    In the first part of the thesis potential drug targets in Leishmania parasites were identified and hits against these targets were thereafter suggested. In paper I bioinformatics together with experimental work were used to evaluate lateral gene transfer (LGT) in genus Leishmania. LGTs of prokaryote origin often lack human homologs, and are therefore hypothesized to be valuable drug targets. LGT in genus Leishmania is shown to be a dynamic process in which some acquired genes are conserved in the recipient genomes and others are degraded and eventually lost. Some LGTs have also undergone pseudogenization. It is thus important to evaluate LGT products before exploring them as potential drug targets.

    In paper II ligand-based virtual screening and molecular docking were used to suggest potential hits against the LGT product pteridine reductase 1 (PTR1) and the two-domain enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) both involved in folate metabolism. DHFR-TS is not encoded by an LGT but it has been hypothesised that several enzymes in the folate pathway need to be inhibited to affect the viability of Leishmania parasites. One potential hit compound against PTR1 and the DHFR-domain and four hit compounds against PTR1 and the TS-domain were identified and tested on Leishmania tropica promastigotes. The suggested PTR1/TS inhibitors had no effect in the promastigote assay, however one of them enhanced the effect of the PTR1/DHFR inhibitor, which also had effect on its own.

    In the second part of the project, focus shifted towards predictions of targets for compounds with known anti-leishmanial activity but unknown mechanisms of actions. In paper III a ligand-based-target fishing (LBTF) method was developed. The reference compounds were metabolites to metabolic enzymes and similarities were assessed with Euclidean distance calculations in chemical property space. The LBTF approach was used to suggest potential targets to a set of anti-leishmanial agents retrieved from ChEMBL-database. The theory behind the LBTF method developed in paper III was also used in paper IV to predict targets of two sponge-derived alkaloids that where shown to have anti-leishmanial activity.

    List of papers
    1. The Dynamics of Lateral Gene Transfer in Genus Leishmania - A Route for Adaptation and Species Diversification
    Open this publication in new window or tab >>The Dynamics of Lateral Gene Transfer in Genus Leishmania - A Route for Adaptation and Species Diversification
    2016 (English)In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 10, no 1, article id e0004326Article in journal (Refereed) Published
    Abstract [en]

    Background The genome of Leishmania major harbours a comparably high proportion of genes of prokaryote origin, acquired by lateral gene transfer (LGT). Some of these are present in closely related trypanosomatids, while some are detected in Leishmania only. We have evaluated the impact and destiny of LGT in genus Leishmania. Methodology/Principal Findings To study the dynamics and fate of LGTs we have performed phylogenetic, as well as nucleotide and amino acid composition analyses within orthologous groups of LGTs detected in Leishmania. A set of universal trypanosomatid LGTs was added as a reference group. Both groups of LGTs have, to some extent, ameliorated to resemble the recipient genomes. However, while virtually all of the universal trypanosomatid LGTs are distributed and conserved in the entire genus Leishmania, the LGTs uniquely present in genus Leishmania are more prone to gene loss and display faster rates of evolution. Furthermore, a PCR based approach has been employed to ascertain the presence of a set of twenty LGTs uniquely present in genus Leishmania, and three universal trypanosomatid LGTs, in ten additional strains of Leishmania. Evolutionary rates and predicted expression levels of these LGTs have also been estimated. Ten of the twenty LGTs are distributed and conserved in all species investigated, while the remainder have been subjected to modifications, or undergone pseudogenization, degradation or loss in one or more species. Conclusions/Significance LGTs unique to the genus Leishmania have been acquired after the divergence of Leishmania from the other trypanosomatids, and are evolving faster than their recipient genomes. This implies that LGT in genus Leishmania is a continuous and dynamic process contributing to species differentiation and speciation. This study also highlights the importance of carefully evaluating these dynamic genes, e.g. as LGTs have been suggested as potential drug targets.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-294607 (URN)10.1371/journal.pntd.0004326 (DOI)000372565700039 ()26730948 (PubMedID)
    Funder
    Swedish Research Council Formas, 2008-1366
    Available from: 2016-05-26 Created: 2016-05-25 Last updated: 2018-12-05Bibliographically approved
    2. Multi-targeting the folate pathway is a promising strategy against Leishmania tropica
    Open this publication in new window or tab >>Multi-targeting the folate pathway is a promising strategy against Leishmania tropica
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-367381 (URN)
    Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05
    3. Prediction of anti-leishmanial drug targets using metabolite-based target fishing
    Open this publication in new window or tab >>Prediction of anti-leishmanial drug targets using metabolite-based target fishing
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-368497 (URN)
    Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05
    4. Aaptamines from Haliclona and bromopyrroles from Agelas — marine sponge alkaloids with distinct modes of action against bacteria and protozoa
    Open this publication in new window or tab >>Aaptamines from Haliclona and bromopyrroles from Agelas — marine sponge alkaloids with distinct modes of action against bacteria and protozoa
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-368498 (URN)
    Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-20
  • 326.
    Vikeved, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Alsmark, UCM
    Uppsala University.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Prediction of anti-leishmanial drug targets using metabolite-based target fishingManuscript (preprint) (Other academic)
  • 327.
    Vikeved, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Alsmark, UCM
    Uppsala University.
    Multi-targeting the folate pathway is a promising strategy against Leishmania tropicaManuscript (preprint) (Other academic)
  • 328. Villela, Daniel
    et al.
    Leonhardt, Julia
    Patel, Neal
    Joseph, Jason
    Kirsch, Sebastian
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unger, Thomas
    Bader, Michael
    Santos, Robson A
    Sumners, Colin
    Steckelings, U Muscha
    Angiotensin type 2 receptor (AT2R) and receptor Mas: a complex liaison2015In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 128, no 4, p. 227-234Article, review/survey (Refereed)
    Abstract [en]

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking similarities. Moreover, in some instances, antagonists for one receptor are able to inhibit the action of agonists for the respective other receptor. These observations suggest that there may be a functional or even physical interaction of both receptors. This article discusses potential mechanisms underlying the phenomenon of blockade of angiotensin-(1-7) [Ang-(1-7)] actions by AT2R antagonists and vice versa. Such mechanisms may comprise dimerization of the receptors or dimerization-independent mechanisms such as lack of specificity of the receptor ligands used in the experiments or involvement of the Ang-(1-7) metabolite alamandine and its receptor MrgD in the observed effects. We conclude that evidence for a functional interaction of both receptors is strong, but that such an interaction may be species- and/or tissue-specific and that elucidation of the precise nature of the interaction is only at the very beginning.

  • 329.
    Wallinder, Charlotta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Botros, Milad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Guimond, Marie-Odile
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gallo-Payet, Nicole
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands2015In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 6, no 2, p. 178-182Article in journal (Refereed)
    Abstract [en]

    Migration of the methylene imidazole side chain in the first reported selective drug-like AT, receptor agonist C21/M024 (1) delivered the AT, receptor antagonist C38/M132 (2). We now report that the AT, receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.

  • 330. Wang, Likui
    et al.
    Gao, Shijuan
    Jiang, Wei
    Luo, Cheng
    Xu, Maonian
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosendahl, Markus
    Huang, Wenlin
    Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration2014In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 15, no 9, p. 16226-16245Article, review/survey (Refereed)
    Abstract [en]

    Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair.

  • 331.
    Wannberg, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-Assisted Synthesis of C2-Symmetric HIV-1 Protease Inhibitors: Development and Applications of In Situ Carbonylations and other Palladium(0)-Catalyzed Reactions2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The HIV protease is an essential enzyme for HIV replication and constitutes an important target in the treatment of HIV/AIDS. Efficient combination therapies using inhibitors of the reverse transcriptase and protease enzymes have led many to reevaluate HIV infections from a terminal condition to a chronic-but-manageable disease in the developed world. Unfortunately, the emergence of drug resistant viral strains and severe treatment-related adverse effects limit the benefits of current anti-HIV/AIDS drugs for many patients. Furthermore, less than one in ten patients infected with HIV in low- and middle-income countries have access to proper treatment. These important shortcomings highlight the need for new, cost effective anti-HIV/AIDS drugs with unique properties.

    Microwave heating has recently emerged as a productivity-enhancing tool for the medicinal chemist. Reaction times can often be reduced from hours to minutes or seconds and chemistry previously considered impractical or unattainable can now be accessed.

    In this thesis, the search for unique HIV-1 protease inhibitors and the development and application of new microwave-promoted synthetic methods useful in small-scale medicinal chemistry applications are presented. Protocols for rapid amino- and hydrazidocarbonylations were developed. Mo(CO)6 was used as a solid source of carbon monoxide, enabling a safe, efficient and simple way to exploit carbonylation chemistry without the direct use of toxic carbon monoxide gas. The aminocarbonylation methodology was applied in the synthesis of two series of new HIV-1 protease inhibitors. A biological evaluation suggested that ortho-substitution of P1 and/or P1’ benzyl side chains might provide a new approach to HIV-1 protease inhibitors with novel properties. To assess the scope and limitations of the ortho-substitution concept, a new series of compounds exhibiting fair potency was prepared by various microwave-heated, palladium-catalyzed coupling reactions. Finally, computer modeling was applied to rationalize the binding-modes and structure-activity relationships of these HIV-1 protease inhibitors.

    List of papers
    1. Increasing Rates and Scope of Reactions: Sluggish Amines in Microwave-Heated Aminocarbonylation Reactions under Air
    Open this publication in new window or tab >>Increasing Rates and Scope of Reactions: Sluggish Amines in Microwave-Heated Aminocarbonylation Reactions under Air
    2003 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 68, no 14, p. 5750-5753Article in journal (Refereed) Published
    Abstract [en]

    Commercially available molybdenum hexacarbonyl serves as a convenient and solid carbon monoxide source in palladium-catalyzed aminocarbonylations of aryl bromides and iodides. This improved microwave protocol, relying on DBU as base and THF as solvent, enables rapid couplings using otherwise sluggish anilines, tert-butylamine, and free amino acids. In addition, Cr(CO)6 and W(CO)6 were found to be useful alternative CO-releasing reagents. Altogether, 16 different aromatic amides were synthesized under air in 35−95% yield after only 15 min of controlled microwave irradiation.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-93072 (URN)10.1021/jo034382d (DOI)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    2. Direct Microwave Synthesis of N,N'-diacylhydrazines and Boc-protected Hydrazides by in situ Carbonylations under Air
    Open this publication in new window or tab >>Direct Microwave Synthesis of N,N'-diacylhydrazines and Boc-protected Hydrazides by in situ Carbonylations under Air
    2004 (English)In: Synlett, p. 2335-2338Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93073 (URN)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2013-07-04Bibliographically approved
    3. Microwave-Enhanced and Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template
    Open this publication in new window or tab >>Microwave-Enhanced and Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template
    2005 (English)In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 7, no 4, p. 574-583Article in journal (Refereed) Published
    Abstract [en]

    Progress in organometallic catalysis and recent advancements in the development of carbonylative reaction protocols without direct use of carbon monoxide have been utilized for efficient functionalizations of 4-aryl-dihydropyrimidone structures. The use of modern microwave technology enabled both high reaction rates and convenient handling. Examples of palladium-catalyzed cross-couplings, Heck reactions, amino- and alkoxycarbonylations, and direct N-amidations of 4-(bromophenyl)-dihydropyrimidones were performed. Further, the first N3-arylations of the dihydropyrimidone ring system were successfully completed using the copper-catalyzed Goldberg reaction. Altogether, these protocols provide new tools for rapid generation of novel and diverse dihydropyrimidone derivatives.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-93074 (URN)16004501 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2018-01-13Bibliographically approved
    4. High-Speed Synthesis of Potent C2-Symmetric HIV-1 Protease Inhibitors by in Situ Aminocarbonylations
    Open this publication in new window or tab >>High-Speed Synthesis of Potent C2-Symmetric HIV-1 Protease Inhibitors by in Situ Aminocarbonylations
    Show others...
    2005 (English)In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 7, no 4, p. 611-617Article in journal (Refereed) Published
    Abstract [en]

    Two novel series of C2-symmetric HIV-1 protease inhibitors were synthesized by microwave-promoted, palladium-catalyzed aminocarbonylations of the o-iodo- and m-bromobenzyloxy P1/P1' substituted core structures. Molybdenum hexacarbonyl was used as a convenient solid source of carbon monoxide in these transformations. After the initial high-speed library generation, biological testing identified highly active HIV-1 protease inhibitors. Selected ortho- and meta-decorated inhibitors were subsequently resynthesized on a larger scale and retested for their affinity toward HIV-1 protease, showing micromolar to low nanomolar inhibition. The discovery of highly active inhibitors containing large phenyl amide ortho substituents in the P1/P1' positions indicates that larger groups than previously believed are tolerated in this part of the S1/S1' pocket.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93075 (URN)16004505 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    5. A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
    Open this publication in new window or tab >>A New Structural Theme in C2-Symmetric HIV-1 Protease Inhibitors: ortho-Substituted P1/P1’ Side Chains
    Show others...
    2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, p. 5303-5315Article in journal (Refereed) Published
    Abstract [en]

    In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon-carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1' side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure-activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1' groups of which two seem more plausible.

    Keywords
    Amides/chemical synthesis/*chemistry/pharmacology, Catalysis, Computer Simulation, Crystallography; X-Ray, Drug Design, HIV Protease/*chemistry/drug effects, HIV Protease Inhibitors/*chemical synthesis/*chemistry/pharmacology, Microwaves, Models; Molecular, Molecular Structure, Palladium/chemistry, Quantitative Structure-Activity Relationship, Stereoisomerism
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93076 (URN)16621572 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
  • 332.
    Wannberg, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dallinger, Doris
    Kappe, C. Oliver
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-Enhanced and Metal-Catalyzed Functionalizations of the 4-Aryl-Dihydropyrimidone Template2005In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 7, no 4, p. 574-583Article in journal (Refereed)
    Abstract [en]

    Progress in organometallic catalysis and recent advancements in the development of carbonylative reaction protocols without direct use of carbon monoxide have been utilized for efficient functionalizations of 4-aryl-dihydropyrimidone structures. The use of modern microwave technology enabled both high reaction rates and convenient handling. Examples of palladium-catalyzed cross-couplings, Heck reactions, amino- and alkoxycarbonylations, and direct N-amidations of 4-(bromophenyl)-dihydropyrimidones were performed. Further, the first N3-arylations of the dihydropyrimidone ring system were successfully completed using the copper-catalyzed Goldberg reaction. Altogether, these protocols provide new tools for rapid generation of novel and diverse dihydropyrimidone derivatives.

  • 333.
    Wannberg, Johan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Isaksson, Rebecka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Bremberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes2018In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 3, p. 519-522Article in journal (Refereed)
    Abstract [en]

    A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

  • 334.
    Wedén, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Larsson, Sonny
    Jodrell Laboratory, Royal Botanic Garden, Kew, UK.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    The edible truffle Choiromyces venosus and its use in Sweden2009In: Acta Botanica Yunnanica, ISSN 0253-2700, Vol. 31, no S16, p. 94-96Article in journal (Refereed)
    Abstract [en]

    The ascomycete truffle Choiromyces venosus is still largely unknown with respect to its biology, ecology and physiology. C. venosus has been collected and consumed as a delicacy in Sweden for at least 100 years. The species was first described by Fries in 1830 , and has been regarded synonymous with C. meandriformis, described by Vittadini 1831. In southern Europe there is a widespread belief that C. venosus is toxic to humans, but no record of C. venosus poisoning has ever been reported from northern Europe. Whether there is a taxonomic/phylogenetic explanation underlying the different traditions in different parts of Europe is currently under investigation. Our studies in this field include cytotoxicity data and are under completion. This is a highly important aspect in the attempts to establish a new cash crop. Preliminary results indicate that the amounts of C. venosus extract required to achieve cell death in the cytotoxicity assay is similar to that of other commonly consumed fungi including Agaricus bisporus and Tuber aestivum.

  • 335. Wensbo, David
    et al.
    Xin, Tao
    Stefanac, Tomislav
    Arora, Jalaj
    Edwards, Louise
    Isaac, Methvin
    Slassi, Abdelmalik
    Stormann, Thomas M.
    McLeod, Donald A.
    Kers, Annika
    Malmberg, Johan
    Oscarsson, Karin
    Gyback, Helena
    Johansson, Martin
    Minidis, Alexander
    Waldman, Mangus
    Yngve, Ulrika
    Osterwall, Christoffer.
    Preparation of five-membered heterocyclic compounds as mGluR5 receptor antagonists.2004Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present invention relates to five-membered heterocyclic compds. (shown as I; variables defined below; e.g. II), a process for their prepn. and new intermediates prepd. therein, pharmaceutical formulations contg. said compds. and to the use of said compds. in therapy, e.g. neurol., psychiatric and chronic and acute pain disorders (no data). Typical IC50 values for mGluR5 receptor antagonist activity are ≤10 μM; no values for individual compds. are given. Methods of prepn. are claimed and example prepns. and/or characterization data are included for ∼800 examples of I and intermediates. For example, [3-[3-[[[4-methyl-5-(thiophen-2-yl)-4H-[1,2,4]triazol-3-yl]sulfanyl]methyl][1,2,4]oxadiazol-5-yl]phenyl]carbamic acid tert-Bu ester was prepd. in 79% yield by condensation of 4-methyl-5-(thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol with [3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)phenyl]carbamic acid tert-Bu ester in MeCN in the presence of K2CO3. For I: P = H, C3-7alkyl or a 3- to 8-membered ring contg. ≥1 atoms = C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring contg. ≥1 C, N, O and S; R1 = H, hydroxy, halo, nitro, C1-6-alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, etc. and a 5- or 6-membered ring contg. ≥1 C, N, O and S, wherein said ring may be substituted by ≥1 A. M1 = a bond, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C0-4alkyl(CO)C0-4alkyl, C0-3alkylOC0-3alkyl, C0-3alkyl(CO)NR5, C0-3alkyl(CO)NR5C0-3alkyl, C0-4-alkylNR5, C0-3alkylSC0-3alkyl, etc.; R2 = H, hydroxy, C0-6alkylcyano, oxo, NR5, NOR5, C1-4alkylhalo, halo, C1-4alkyl, etc. X1, X2 and X3 = CR, CO, N, NR, O and S; R = H, C0-3alkyl, halo, C0-3alkylOR5, C0-3-alkylNR5R6, C0-3alkyl(CO)OR5, C0-3alkylNR5R6 and C0-3alkylaryl; M2 = a bond, C1-3alkyl, C3-7cycloalkyl, C2-3alkenyl, C2-3alkynyl, C0-4alkyl(CO)C0-4alkyl, C0-3alkylOC0-3alkyl, etc.; R3 = H, hydroxy, C0-6alkylcyano, oxo, NR, NOR5, C1-4alkylhalo, halo, C1-4alkyl, etc. X4 = C0-4alkylR5, C0-4alkyl(NR5R6), C0-4-alkyl(NR5R6):N, NR5C0-4alkyl(NR5R6):N, NOC0-4alkyl, C1-4alkylhalo, C, O, SO, SO2 and S; Q is a 5- or 6-membered ring contg. ≥1 C, N, O and S, which group may optionally be fused with a 5- or 6-membered ring contg. ≥1 C, N, O and S and which fused ring may be substituted by ≥1 A. R4 = H, hydroxy, C0-6alkylcyano, oxo, NR5, NOR5, C1-4alkylhalo, halo, C1-4alkyl, OC1-4alkyl, OC0-6alkylaryl, etc. and a 5- or 6-membered ring contg. ≥1 atoms = C, N, O or S, wherein said ring may be substituted by ≥1 A; R5, R6 = H, OH, C1-6alkyl, etc.; A = H, OH, O, halo, nitro, C0-6alkylcyano, etc.; m = 0-4; and n = 0-3; addnl. details are given in the claims. [on SciFinder(R)]

  • 336.
    Wetzel, Alexander
    et al.
    AstraZeneca, Dept Med Chem, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Pepparedsleden 1, SE-43183 Molndal, Sweden.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Pepparedsleden 1, SE-43183 Molndal, Sweden.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brånalt, Jonas
    AstraZeneca, Dept Med Chem, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Pepparedsleden 1, SE-43183 Molndal, Sweden.
    Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki-Heck Reactions.2017In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 7, p. 1602-1605Article in journal (Refereed)
    Abstract [en]

    Pd(0)-catalyzed Mizoroki-Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors.

  • 337.
    Wolff, Anette
    et al.
    Lund University.
    Antfolk, Maria
    Lund University.
    Brodin, Birger
    Copenhagen University.
    Tenje, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    In vitro blood-brain barrier models: An overview of established models and new microfluidic approaches2015In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 9, p. 2727-2746Article in journal (Refereed)
    Abstract [en]

    The societal need for new central nervous system (CNS) medicines is substantial, because of the global increase in life expectancy and the accompanying increase in age-related CNS diseases. Low blood-brain barrier (BBB) permeability has been one of the major causes of failure for new CNS drug candidates. There has therefore been a great interest in cell models, which mimic BBB permeation properties. In this review, we present an overview of the performance of monocultured, cocultured, and triple-cultured primary cells and immortalized cell lines, including key parameters such as transendothelial electrical resistance values, permeabilities of paracellular flux markers, and expression of BBB-specific marker proteins. Microfluidic systems are gaining ground as a new automated technical platform for cell culture and systematic analysis. The performance of these systems was compared with current state-of-the-art models and it was noted that, although they show great promise, these systems have not yet reached beyond the proof-of-concept stage. In general, it was found that there were large variations in experimental protocols, BBB phenotype markers, and paracellular flux markers used. It is the author's opinion that the field may benefit greatly from developing standardized methodologies and initiating collaborative efforts on optimizing culture protocols.

  • 338. Wu, F
    et al.
    Lendvai, G
    Yngve, U
    Eriksson, B
    Langstrom, B
    Bergstrom, M
    Hybridisation of [Br-76]-labelled antisense oligonucleotides to Chromogranin A mRNA verified by RT-PCR2004In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 31, no 8, p. 1073-1078Article in journal (Refereed)
    Abstract [en]

    Methods have been developed to label oligonucleotides (ODNs) in the 5'-position with Br-76 via a prosthetic group on a hexylamino-linker. The purpose of the study was to explore whether the labelling procedure would prevent specific hybridisation by using reverse transcription-polymerase chain reaction (RT-PCR) followed by sequencing of the PCR product. Antisense ODNs (30 mer, specific for rat Chromogranin A [CgA] mRNA) with phosphodiester (O-ODN) or phosphothiciate (S-ODN) backbone, either unlabelled or labelled with Br-76, served as one of the primers in individual PCR reactions. Using O-ODN as a primer, irrespective of being labelled or not, a selected 225-bp PCR fragment was successfully amplified. However, no amplification was obtained using S-ODN as a primer. The proper PCR products were only detected in the sample prepared from the adrenal gland, but not in that from the heart, liver or kidney. Autoradiographic recording of the gel, after gel electrophoresis, revealed radioactive signals corresponding to the amplified PCR products. The sequence of the PCR product matched the rat CgA mRNA sequence obtained from the EMBL database. RT-PCR is an attractive method to identify the selective binding of modified ODNs to target mRNA. This method confirmed that the labelling with Br-76 did not change the hybridisation ability of antisense O-ODN. (C) 2004 Elsevier Inc. All rights reserved.

  • 339.
    Wu, Xiongyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Öhrngren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Joshi, Advait A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Trejos, Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Persson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Arvela, Riina K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wallberg, Hans
    Medivir AB.
    Vrang, Lotta
    Medivir AB.
    Rosenquist, Åsa
    Medivir.
    Samuelsson, Bertil
    Medivir AB.
    Unge, Johan
    Lund University, MAX IV-laboratory .
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, p. 2724-2736Article in journal (Refereed)
    Abstract [en]

    In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

  • 340.
    Wulff, Marie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Studies on structure and mechanism at formation of solid solutions and solid dispersions of hydrophobic drugs in polymers1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of the studies was to investigate the structures formed and mechanisms involved, when a hydrophobic drug is dispersed in a polymer carrier. The effect of different additives, like surfactants and cyclodextrins, was evaluated. The dispersions were prepared by the melting method. The phase composition and structure of the samples were studied by X-ray powder diffraction (XRD) and solid-state NMR. The thermal analysis was made by differential scanning calorimetry (DSC) and temperature-modulated DSC (MTDSC).

    The structure of the systems formed upon addition of surfactants was found to depend on several factors. The critical surfactant concentration for formation of solid solutions with different counterions correlated very well to the relative size of the counterions. The ion with the highest charge-to-radius ratio, Li+, formed bonds that were different from those formed with the Na+ and K+ ions. This could explain the observed increased crystallinity and the deviation in the thermal behavior of the Li+ compounds, compared to that obtained for the Na+ and K+ systems.

    The critical surfactant concentrations in different PEGs were correlated to the structure of the PEGs. The polymers contained varying amounts of folded and extended chains, which influences the amorphous parts of the polymer structure, where the surfactant-drug aggregates are likely to dissolve. The solid solubility of griseofulvin was found to be much higher in PEG 6000 than in PEG 3000 or PEG 20000 with surfactant added, implying that a certain balance between the amount of folded chains and surfactant concentration is crucial for the creation of the solid solution. The prerequisites of the formation of a solid solution were given already in the melt.

    The melting method was introduced as a new method for producing cyclodextrin (CD) inclusion complexes of hydrophobic drugs. The structures formed when cyclodextrins were added to the solid dispersions depended on the character of the CD. The results demonstrated the different competition between the polymer, the drug and the CDs when forming bonds to each other. Since the interaction between α-CD and PEG is stronger than between β-CD and the polymer, β-CD can form a stronger bond to indomethacin (IM) than α-CD. In the γ-CD case, a new phase with tetragonal structure was formed where the indomethacin molecule was bound to the CD in an inclusion complex. The interactions resulted in a delayed release of indomethacin from PEG 6000 in the order α-CD < γ-CD <=CD.

    The specific information on the relative crystallinity obtained by the NMR, XRD, DSC and MTDSC techniques was emphasized for the γ-CD system.

    The selection of operational parameters for proper measurements by MTDSC is crucial. A dimensionless quantity, degree of oscillation, was introduced to be able to predict the reproducibility of the heat of fusion determinations. A degree of oscillation ~1-2 gave reliable results for a variety of combinations for the systems examined. With proper operational settings MTDSC can be used for determining the relative crystallinity of certain compounds. It is recommended to test a number of variations of the parameters whenever examining a new type of sample.

  • 341.
    Wångsell, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Design and Synthesis of Aspartic and Serine Protease Inhibitors: Targeting the BACE-1 and the HCV NS3 Protease2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes work done to design and synthesize protease inhibitors, with the intention of developing therapeutic agents for Alzheimer’s disease (AD) and the chronic liver condition caused by infection of the hepatitis C virus (HCV). AD is the most common form of dementia, and HCV infection is the primary reason for liver transplantation in industrialized countries. Today, these two illnesses affect 24 and 170 million people, respectively. It has been shown that the human aspartic protease BACE-1 plays an important role in the development of AD, and thus inhibition of BACE-1 may offer a way to improve the quality of life of individuals afflicted with the disease. Furthermore, it is known that the serine protease NS3 is a vital component in the replication of HCV.

    Several novel potent BACE-1 inhibitors encompassing different transition state mimics were prepared. First, a hydroxyethylene moiety encompassing a secondary hydroxyl group was evaluated as a transition state analogue, producing inhibitors in the low nanomolar range. Various tertiary hydroxyl isosteres were also investigated as the central core, with the aim of shielding the pivotal hydroxyl group. These transition state isosteres consisted of tertiary hydroxyl analogues of previously used secondary hydroxyl containing norstatine, statine, and hydroxyethylamine isosteres. Several tertiary hydroxyl-containing inhibitors were found to be active in the low micromolar range. In addition, two inhibitors were co-crystallized with the BACE-1 enzyme to provide X-ray crystal structures, which furnished valuable binding information for further design of improved BACE-1 inhibitors.

    The goal in the HCV NS3 protease inhibitor project was to design, synthesize and evaluate a novel hydroxycyclopentene bioisostere to the previously used acyl-hydroxyproline moiety. The investigation revealed that it was possible to synthesize inhibitors containing this new bioisostere that were potent in the low nanomolar range. Further optimization by rigidification of the most active inhibitor resulted in equipotent macrocyclic compounds.

    List of papers
    1. Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
    Open this publication in new window or tab >>Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
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    2010 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 3, p. 870-882Article in journal (Refereed) Published
    Abstract [en]

    We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2′-P3′ position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1′-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 value of 3.1 nM.

    Keywords
    Alzheimer's disease, BACE-1 inhibitors, Hydroxylethylene, Transition state isostere
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-109028 (URN)10.1016/j.ejmech.2009.11.013 (DOI)000275404900003 ()20036448 (PubMedID)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    2. Design and synthesis of BACE-1 inhibitors utilizing a tertiary hydroxyl motif as the transition state mimic
    Open this publication in new window or tab >>Design and synthesis of BACE-1 inhibitors utilizing a tertiary hydroxyl motif as the transition state mimic
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    2009 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, no 16, p. 4711-4714Article in journal (Refereed) Published
    Abstract [en]

    Two series of drug-like BACE-1 inhibitors with a shielded tertiary   hydroxyl as transition state isostere have been synthesized. The most   potent inhibitor exhibited a BACE-1 IC50 value of 0.23 mu M.

    Place, publisher, year, edition, pages
    Elsevier, 2009
    Keywords
    Alzheimer's disease, BACE-1, Enzyme inhibitor, Transition state mimetic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-109025 (URN)10.1016/j.bmcl.2009.06.065 (DOI)000268358800039 ()
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2018-01-13Bibliographically approved
    3. Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
    Open this publication in new window or tab >>Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
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    2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 1, p. 145-155Article in journal (Refereed) Published
    Abstract [en]

    Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

    Keywords
    α-Benzylnorstatine, α-Phenylnorstatine, Alzheimer's disease, BACE-1 inhibitors, tert-Hydroxyl, Transition state mimic
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-109026 (URN)10.1016/j.bmc.2010.11.042 (DOI)000285724800014 ()21183353 (PubMedID)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2018-01-13Bibliographically approved
    4. Synthesis and evaluation of a new class of tertiary alcohol based BACE-1 inhibitors
    Open this publication in new window or tab >>Synthesis and evaluation of a new class of tertiary alcohol based BACE-1 inhibitors
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    2009 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, no 48, p. 10047-10059Article in journal (Refereed) Published
    Abstract [en]

    BACE-1 has emerged as one of the best characterized targets for future   Alzheimer therapy. In accordance with the successful identification of   masked inhibitors of HIV-1 protease, we envisioned that tert-alcohol   containing transition-state mimicking structures would also be   worthwhile evaluating as BACE-1 inhibitors. Twelve novel inhibitors   were prepared via synthetic routes using epoxyalcohol derivates as key   intermediates. The best synthesized tert-hydroxy inhibitor exhibited a   BACE-1 IC50 value of 0.38 mu M.

    Keywords
    Alzheimer's disease, BACE-1 inhibitors, Transitions state isostere
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-109024 (URN)10.1016/j.tet.2009.09.106 (DOI)000271841700018 ()
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2018-01-13Bibliographically approved
    5. Synthesis of novel potent hepatitis C virus NS3 protease inhibitors: discovery of 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a N-acyl-L-hydroxyproline bioisostere
    Open this publication in new window or tab >>Synthesis of novel potent hepatitis C virus NS3 protease inhibitors: discovery of 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a N-acyl-L-hydroxyproline bioisostere
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    2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 2, p. 827-838Article in journal (Refereed) Published
    Abstract [en]

    Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a Ki value of 1.1 nM.

    Keywords
    Cyclopentanes/*chemical synthesis/*pharmacology, Dicarboxylic Acids/*chemical synthesis/*pharmacology, Indicators and Reagents, Kinetics, Magnetic Resonance Spectroscopy, Models; Molecular, Protease Inhibitors/*chemical synthesis/*pharmacology, Stereoisomerism, Structure-Activity Relationship, Viral Nonstructural Proteins/*antagonists & inhibitors
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-17096 (URN)10.1016/j.bmc.2006.10.044 (DOI)000243315300021 ()17107807 (PubMedID)
    Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2018-01-12Bibliographically approved
    6. Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs
    Open this publication in new window or tab >>Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs
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    2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 7184-7202Article in journal (Refereed) Published
    Abstract [en]

    Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a Ki value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

    Keywords
    Cyclopentane and Cyclopentene derived P2 templates, HCV, Macrocyclic inhibitors, NS3 protease
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-17095 (URN)10.1016/j.bmc.2007.07.027 (DOI)000250324900030 ()17845856 (PubMedID)
    Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2018-01-12Bibliographically approved
  • 342.
    Yang, Zhenlin
    et al.
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China.
    Han, Shuo
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China.
    Keller, Max
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Kaiser, Anette
    Bender, Brian J.
    Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA.
    Bosse, Mathias
    Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany.
    Burkert, Kerstin
    Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany.
    Koegler, Lisa M.
    Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany.
    Wifling, David
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Bernhardt, Guenther
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Plank, Nicole
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Littmann, Timo
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Schmidt, Peter
    Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany.
    Yi, Cuiying
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China.
    Li, Beibei
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China.
    Ye, Sheng
    Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China.
    Zhang, Rongguang
    Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China;Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai, Peoples R China.
    Xu, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stevens, Raymond C.
    ShanghaiTech Univ, Human Inst, Shanghai, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China.
    Huster, Daniel
    Univ Leipzig, Inst Med Phys & Biophys, Leipzig, Germany.
    Meiler, Jens
    Vanderbilt Univ, Dept Pharmacol, Struct Biol Ctr, Nashville, TN USA;Vanderbilt Univ, Struct Biol Ctr, Dept Chem, 221 Kirkland Hall, Nashville, TN 37235 USA;Vanderbilt Univ, Dept Bioinformat, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA.
    Zhao, Qiang
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China.
    Beck-Sickinger, Annette G.
    Univ Leipzig, Inst Biochem, Fac Life Sci, Leipzig, Germany.
    Buschauer, Armin
    Univ Regensburg, Inst Pharm, Pharmaceut Med Chem 2, Regensburg, Germany.
    Wu, Beili
    Chinese Acad Sci, Shanghai Inst Mat Medica, Key Lab Receptor Res, Shanghai, Peoples R China;Univ Chinese Acad Sci, Beijing, Peoples R China;ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China;Chinese Acad Sci, Ctr Excellence Biomacromol, Beijing, Peoples R China.
    Structural basis of ligand binding modes at the neuropeptide Y Y-1 receptor2018In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 556, no 7702, p. 520-524Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology(1,2). The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y-1, Y-2, Y-4 and Y-5 receptors, with different affinity and selectivity(3). NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y-1 receptor (Y1R)(4). A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity(4), tumour(1) and bone loss(5). However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability(6). Here we report crystal structures of the human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 angstrom resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y1R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery that targets NPY receptors.

  • 343. Yngve, Ulrika
    et al.
    Söderman, Peter
    Svensson, Mats
    Rosqvist, Susanne
    Arvidsson, Per I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Imidazopyridine-based inhibitors of glycogen synthase kinase 3: synthesis and evaluation of amide isostere replacements of the carboxamide scaffold2012In: Chemistry and Biodiversity, ISSN 1612-1872, E-ISSN 1612-1880, Vol. 9, no 11, p. 2442-2452Article in journal (Refereed)
    Abstract [en]

    In this study, we explored the effect of bioisostere replacement in a series of glycogen synthase kinase 3 (GSK3) inhibitors based on the imidazopyridine core. The synthesis and biological evaluation of a number of novel sulfonamide, 1,2,4-oxadiazole, and thiazole derivates as amide bioisosteres, as well as a computational rationalization of the obtained results are reported.

  • 344.
    Yu, Zuoxiang
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Direct injection of plasma samples into restricted-access media precolumns for drug analysis in column-switching systems1997Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on the theoretical and practical aspects of using column-switching systems for direct injection of plasma samples to assay drugs at ng/ml levels. The systems utilized a restricted-access media (RAM) precolumn for the sample clean-up and trace enrichment. The separation of analytes of interest was accomplished on a reversed-phase analytical column via a switching device in the back-flush mode.

    Retention principles for the functional permission of direct injection of biological samples on RAMs were proposed. In the long course of plasma injections, RAM packings behaved distinctly different from conventional reversed-phase materials. Changes of retention, peak performance and column resistance after the injection of 10-20 ml of plasma were mainly resulted from the blockage of sealings or the adsorption of proteins on the hydrophilic layer of the packings.

    The clean-up effect, the stability of the system and the choice of UV wavelength depended on the character of the RAM packings. However, the composition of the mobile phase serving for the RAM columns could affect the plasma elution profile, the recovery of plasma matrix and column lifetime.

    Based on the developed systems, a detection limit of 10 ng/ml was obtained for the determination of weakly UV absorbing local anaesthetics with UV at 210 nm in conjunction with large volumes of plasma injection (500 _l). Analysis of methotrexate and its main metabolite in plasma was achieved with ion-pair conditions using on-line post-column photochemical reaction and fluorimetric detection. The method gave a limit of quantitation of methotrexate at 3.6 ng/ml.

  • 345.
    Zhang, Jian
    et al.
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark..
    Kang, Dongwei
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Bertagnin, Chiara
    Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
    Lu, Huamei
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Kong, Xiujie
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ju, Han
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Lu, Xueyi
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Gao, Ping
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Tian, Ye
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Jia, Haiyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Desta, Samuel
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ding, Xiao
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Sun, Lin
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Fang, Zengjun
    Shandong Univ, Hosp 2, 247 Beiyuan Ave, Jinan 250033, Shandong, Peoples R China..
    Huang, Boshi
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liang, Xuewu
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Jia, Ruifang
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ma, Xiuli
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Xu, Wenfang
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Murugan, Natarajan Arul
    KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Loregian, Arianna
    Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
    Huang, Bing
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Zhan, Peng
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liu, Xinyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and-2 Influenza A Neuraminidases, Including a Drug-Resistant Variant2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 14, p. 6379-6397Article in journal (Refereed)
    Abstract [en]

    On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

  • 346.
    Zhang, Xiaoqun
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Mantas, Ioannis
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Alvarsson, Alexandra
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Yoshitake, Takashi
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomolecular Mass Spectrometry Imaging, National Resource for Mass Spectrometry Imaging, Uppsala, Sweden.
    Pereira, Marcela
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Kehr, Jan
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Millan, Mark J.
    Ctr Rech Croissy, Ctr Therapeut Innovat CNS, Inst Rech Servier, Paris, France..
    Chergui, Karima
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Mol Neurophysiol, Solna, Sweden..
    Svenningsson, Per
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 166Article in journal (Refereed)
    Abstract [en]

    The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (beta-PEA) compared to 3-iodothyronamine (T(1)AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wildtype (WT) and TAAR1 knockout (KO) mice. T(1)AM increased TH phosphorylation at both Ser(19) and Ser(40), actions that should promote functional activity of TH. Indeed, HPLC data revealed higher rates of L-dihydroxyphenylalanine (DOPA) accumulation in WT animals treated with T(1)AM after the administration of a DOPA decarboxylase inhibitor. These effects were abolished both in TAAR1 KO mice and by the TAAR1 antagonist, EPPTB. Further, they were specific inasmuch as Ser(845) phosphorylation of the post-synaptic GluA1 AMPAR subunit was unaffected. The effects of T1AM on TH phosphorylation at both Ser(19) (CamKII-targeted), and Ser40 (PKA-phosphorylated) were inhibited by KN-92 and H-89, inhibitors of CamKII and PKA respectively. Conversely, there was no effect of an EPAC analog, 8-CPT-2Me-cAMP, on TH phosphorylation. In line with these data, T(1)AM increased evoked striatal dopamine release in TAAR1 WT mice, an action blunted in TAAR1 KO mice and by EPPTB. Mass spectrometry imaging revealed no endogenous T(1)AM in the brain, but detected T(1)AM in several brain areas upon systemic administration in both WT and TAAR1 KO mice. In contrast to T1AM, tyramine decreased the phosphorylation of Ser40-TH, while increasing Ser(845)-GluA1 phosphorylation, actions that were not blocked in TAAR1 KO mice. Likewise, beta-PEA reduced Ser(40)-TH and tended to promote Ser845-GluA1 phosphorylation. The D-1 receptor antagonist SCH23390 blocked tyramine-induced Ser(845)-GluA1 phosphorylation, but had no effect on tyramine-or beta-PEA-induced Ser(40)-TH phosphorylation. In conclusion, by intracellular cascades involving CaMKII and PKA, T(1)AM, but not tyramine and beta-PEA, acts via TAAR1 to promote the phosphorylation and functional activity of TH in the dorsal striatum, supporting a modulatory influence on dopamine transmission.

  • 347.
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Overcoming scientific and structural bottlenecks in antibacterial discovery and development2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 170-175Article, review/survey (Refereed)
    Abstract [en]

    Antibiotic resistance is becoming an increasing threat, with too few novel antibiotics coming to market to replace those lost due to resistance development. Efforts by the pharmaceutical industry to screen for and design novel antibacterials have not been successful, with several companies minimizing or closing down their antibacterial research units, leading to a loss of skills and know-how. At the same time, antibiotic innovation in academia is not filling the void due to misaligned incentive structures and lack of vital knowledge of drug discovery. The scientific and structural difficulties in discovering new antibiotics have only begun to be appreciated in the latest years. Part of the problem has been a paradigm shift within both industry and academia to focus on 'rational' drug development with an emphasis on single targets and high-throughput screening of large chemical libraries, which may not be suited to target bacteria. The very particular aspects of 'targeting an organism inside another organism' have not been given enough attention. In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered.

  • 348.
    Åberg, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Combinatorial synthesis of labelled drugs and PET tracers: synthesis of a focused library of 11C-carbonyl-labelled acrylamides as potential biomarkers of EGFR expression2012In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 55, no 14, p. 477-483Article in journal (Refereed)
    Abstract [en]

    Combinatorial synthesis is extensively used in drug development and lead optimisation. However, this approach has rarely been used for positron emission tomography because of limitations in available technologies. [11C]Carbon monoxide is amenable to combinatorial synthesis in transition-metal-catalysed reactions because it can react with a wide variety of electrophiles and nucleophiles, which opens up the possibilities for combinatorial radiochemistry. Herein, we exemplify the combinatorial approach by 11C-labelling a library of epidermal growth factor receptor inhibitors. The selection of candidates was guided by molecular docking. Epidermal growth factor receptor is overexpressed in a variety of tumours, and it has become an important drug target. The 11C-labelling reactions were performed using four substituted vinyl iodides and three different 4-anilino-6-aminoquinazolines using a palladium-mediated reaction with [11C]carbon monoxide using a single set of reaction conditions. In total, 12 labelled acrylamide derivatives were radiolabelled and obtained in 24–61% decay-corrected radiochemical yield (from [11C]carbon monoxide). Starting from 5.6 GBq [11C]carbon monoxide, 0.85 GBq of formulated N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-acryl[11C]amide [11C]12da was obtained within 47 min from end of bombardment (specific activity of 60 GBq µmol−1). This strategy is an example of how [11C]carbon monoxide can be utilised in the labelling of libraries of drug candidates and positron emission tomography tracers for in vitro and in vivo testing.

  • 349.
    Åkerbladh, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(0)-Catalysed Carbonylative Multicomponent Reactions: Synthesis of Heterocycles and the Application of Quinolinyl Pyrimidines as Enzyme Inhibitors2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium-catalysed carbonylative multicomponent reactions have proven useful for the synthesis of structurally diverse compounds. Carbon monoxide serves as an atom-efficient, one-carbon building block, which allows for further structural elaboration of the carbonyl compound. By varying the components of the carbonylative multicomponent reaction, considerable product diversity can readily be attained. However, due to the reluctance to use toxic CO gas, considerable efforts have been directed at exploring non-gaseous approaches. The work described in this thesis has mainly focused on the development of palladium(0)-catalysed, carbonylative multicomponent synthetic methodology, using the non-gaseous CO source molybdenum hexacarbonyl, in the synthesis of heterocycles and other biologically relevant functional groups.

    The first part of this work describes the development of a non-gaseous carbonylative Sonogashira cross-coupling of bifunctional ortho-iodoanilines and terminal alkynes. Where 4-quinolones were synthesised via a carbonylation/cyclisation sequence. Using a similar synthetic strategy, three different N-cyanobenzamide intermediates were prepared by palladium-catalysed carbonylative couplings of various aryl halides and bromides and cyanamide. The formed intermediates provided a basis for further chemical transformations. First, ortho-iodoanilines were carbonylatively coupled with cyanamide and subsequently cyclised to yield heterocyclic 2-aminoquinazolinones. Next, building on those findings, the same synthetic strategy was applied to ortho-halophenols to provide a highly convenient domino carbonylation/cyclisation method for the preparation of benzoxazinones. The developed method was used to evaluate the efficiency of various non-gaseous CO sources. Third, the palladium-catalysed carbonylative synthesis of N-cyanobenzamides, was used to produce biologically relevant N-acylguanidines with considerable product diversity. Finally, one of the developed carbonylative methodologies was used in the preparation of potential NDH-2 inhibitors based on a quinolinyl pyrimidine scaffold. The prepared compounds were biologically evaluated in terms of inhibition of oxidoreductase NDH-2 and antibacterial activity on Gram-negative bacteria, S. aureus and Mtb. The biological evaluation revealed that some of the quinolinyl pyrimidines exerted inhibitory activity on the NDH-2 enzyme and possessed antibacterial properties.

    The work described in this thesis has been devoted to the development of non-gaseous one-pot, multicomponent carbonylation/cyclisation and carbonylation/amination reactions. The described methods offer highly attractive synthetic strategies that can be of great value to synthetic and medicinal chemists.

    List of papers
    1. Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
    Open this publication in new window or tab >>Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
    Show others...
    2015 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, no 3, p. 1464-1471Article in journal (Refereed) Published
    Abstract [en]

    A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products after only 20 min of microwave (MW) heating at 120 degrees C. The second method (B) is a gas-free one-pot two-step sequence which runs at room temperature, allowing the use of sensitive substituents (e.g., nitro and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid source of CO.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-249019 (URN)10.1021/jo502400h (DOI)000349934600019 ()25575042 (PubMedID)
    Available from: 2015-04-24 Created: 2015-04-10 Last updated: 2017-12-04Bibliographically approved
    2. Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide
    Open this publication in new window or tab >>Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide
    2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 7, p. 2966-2973Article in journal (Refereed) Published
    Abstract [en]

    Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2-aminoquinazolinones.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-295556 (URN)10.1021/acs.joc.6b00249 (DOI)000373520200028 ()26967689 (PubMedID)
    Available from: 2016-06-22 Created: 2016-06-08 Last updated: 2017-11-28Bibliographically approved
    3. Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide
    Open this publication in new window or tab >>Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide
    2017 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 6, no 5, p. 620-628Article in journal (Refereed) Published
    Abstract [en]

    A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation-cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)(6) and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzaxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is ex tended to include challenging orthobromophenols. Finally, to highlight the versatility of the developed method, Mo(CO), is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-329967 (URN)10.1002/open.201700130 (DOI)000413038400003 ()29046856 (PubMedID)
    Available from: 2017-09-24 Created: 2017-09-24 Last updated: 2018-02-05Bibliographically approved
    4. Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylguanidines
    Open this publication in new window or tab >>Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylguanidines
    (English)In: Article in journal (Other academic) Submitted
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-329968 (URN)
    Available from: 2017-09-24 Created: 2017-09-24 Last updated: 2017-09-24
    5. Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
    Open this publication in new window or tab >>Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)