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  • 201.
    Muthas, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Development and Application of Computational Methods in Antitubercular Drug Design: Identification of Novel Inhibitors of Ribonucleotide Reductase2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tuberculosis kills approximately 1.7 million people each year around the world making it one of the most lethal infectious diseases. This thesis concerns the development of two computational tools that can support the early stages of drug discovery, and their use in an anti-tubercular drug discovery program.

    One of the tools developed is a statistical molecular design (SMD) approach that generates information-rich libraries biased towards a lead structure. The other metod is a post-filtering technique to increase the success of virtual screening, has also been developed. Both methods have been validated using literature data.

    Ribonucleotide reductase (RNR) has been identified as a potential anti-tubercular target, and our focus has been to develop small-molecule inhibitors of this target. The enzyme consists of two subunits (a large R1 and a small R2 subunit) that have to associate in order to generate a bioactive complex. It had previously been shown that a heptapeptide corresponding to the small R2 subunits C-terminal inhibited the enzyme. In order to investigate the requirements for inhibitory effect of the peptide a library was designed using the developed SMD approach. The designed library was synthesized and evaluated for biological activity and an OPLS-DA model was derived to understand which positions were most important for activity.

    In order to identify small-molecule inhibitors of RNR a combined shape- and structure-based virtual screen was performed, employing ROCS, GlideXP and the developed post-filtering technique. Starting from a library of 1.5 million compounds 24 was acquired and evaluated for enzymatic activity. The best compounds were almost as potent as the starting peptide, but considerably more drug-like.

     

    List of papers
    1. Focused hierarchical design of peptide libraries - follow the lead
    Open this publication in new window or tab >>Focused hierarchical design of peptide libraries - follow the lead
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    2007 (English)In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 21, no 10-11, p. 486-495Article in journal (Refereed) Published
    Abstract [en]

    A novel design strategy based on the hierarchical design of experiments (HDoE) method named focused hierarchical design of experiments (FHDoE) is presented. FHDoE combine two design layers and use focused substitutions to increase the probability of obtaining active peptides when designing libraries through a selection of compounds biased towards a lead structure. Increasing the number of peptides with measurable activity will increase the information gained and the likelihood of constructing good quantitative structure-activity relationship (QSAR) models. The utility of the novel design method is verified using two different approaches. First, a library designed with the novel FHDoE method was compared with libraries generated from classical positional scanning techniques (e.g., alanine scan) as well as with general and centered minimum analog peptide sets (MAPS) libraries by using an example found in the literature. Secondly, the same design strategies were applied to a dataset of 58 angiotensin converting enzyme (ACE) dipeptide inhibitors. QSAR models were generated from designed sublibraries and the activities of the remaining compounds were predicted. These two examples show that the use of FHDoE renders peptide libraries close in physicochemical space to the native ligand, yielding a more thorough screening of the area of interest as compared to the classical positional scans and fractional factorial design (FFD). It is also shown that an FHDoE library of six dipeptides could produce a QSAR model that better described the requisites of high activity ACE inhibitors than could QSAR models built from either a nine-dipeptide library designed with MAPS or a 58-dipeptide library.

    Keywords
    design of experiments, peptide library design, hierarchical design, amino acid z-scales, PCA
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-17025 (URN)10.1002/cem.1069 (DOI)000250873300009 ()
    Available from: 2008-06-15 Created: 2008-06-15 Last updated: 2018-01-12Bibliographically approved
    2. Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
    Open this publication in new window or tab >>Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
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    2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 12, p. 822-832Article in journal (Refereed) Published
    Abstract [en]

    Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that TrP5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain., as compared to Trp5.

    Keywords
    mycobacterium tuberculosis, ribonucleotide reductase, peptide inhibitors, alanine scan, statistical molecular design, structure activity relationships, FHDoE
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-14261 (URN)10.1002/psc.906 (DOI)000252000600007 ()17918768 (PubMedID)
    Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
    3.
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    4. Identification of novel non-peptidic inhibitors of M. tuberculosis ribonucleotide reductase via a combined shape and structure based virtual screen
    Open this publication in new window or tab >>Identification of novel non-peptidic inhibitors of M. tuberculosis ribonucleotide reductase via a combined shape and structure based virtual screen
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    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-99311 (URN)
    Available from: 2009-03-11 Created: 2009-03-11 Last updated: 2010-01-14
  • 202.
    Nazir, Madiha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Senkowski, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nyberg, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Blom, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Mats, Gustafsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Targeting tumor cells based on PDE3A expressionManuscript (preprint) (Other academic)
  • 203.
    Nilsson, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selectivity in Palladium- and Enzyme-Catalyzed Reactions: Focusing on Enhancement of Reactivity2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Catalysis has a profound impact on all living species on the earth. Nature’s catalysts, the enzymes, have the ability to selectively promote a specific bio-chemical transformation, given the required substrate. As well as being highly selective, enzymes enhance the speed of these reactions, helping them to run at temperatures much lower than normally required, i.e. at body temperature. In comparison, reactions used in the production of new materials such as polymers, medicines, fragrances, petrochemicals, etc. are often catalyzed by transition metals. This thesis describes how the selectivity and activity of these catalysts can be influenced via two conceptually different methods: chelation control and microwave heating. The thesis primarily focuses on regio- and stereochemical aspects of the palladium-catalyzed arylation of olefins, i.e. the Heck reaction. Reaction rate enhancement of both palladium and enzyme (polymerase chain reaction [PCR]) catalysis by microwave heating is also discussed.

    Novel chelation-controlled palladium-catalyzed multi- and asymmetric arylations of vinyl ethers were performed, resulting in tetra-substituted olefins as well as chiral quaternary carbon centers with excellent optical purity. In addition, a new synthetic route to diarylated ethanals, relying on a double chelation-controlled regioselective arylation followed by hydrolysis, has been discovered. High temperature conditions, using microwave heating, substantially reduce the reaction time for ligand-controlled asymmetric Heck arylations, while retaining levels of enantioselectivity in most cases. In addition, a potentially useful fast synthetic protocol for the employment of aryl boronic acids in oxidative Heck arylation was developed. Finally, microwave-assisted PCR was described for the first time; this method allows reductions in the run time of 50%.

    List of papers
    1. Highly Regioselective, Sequential and Multiple Palladium-Catalyzed Arylations of Vinyl Ethers Carrying a Coordinating Auxiliary: An Example of a Heck Triarylation Process
    Open this publication in new window or tab >>Highly Regioselective, Sequential and Multiple Palladium-Catalyzed Arylations of Vinyl Ethers Carrying a Coordinating Auxiliary: An Example of a Heck Triarylation Process
    2001 (English)In: Journal of the American Chemical Society, Vol. 123, no 34, p. 8217-8225Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90944 (URN)
    Available from: 2003-10-27 Created: 2003-10-27 Last updated: 2013-07-04Bibliographically approved
    2. A New Highly Asymmetric Chelation-Controlled Heck Arylation
    Open this publication in new window or tab >>A New Highly Asymmetric Chelation-Controlled Heck Arylation
    2003 (English)In: Journal of the American Chemical Society, Vol. 125, no 12, p. 3430-3431Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90945 (URN)
    Available from: 2003-10-27 Created: 2003-10-27 Last updated: 2013-07-04Bibliographically approved
    3. Microwave-Assisted Enantioselective Heck Reactions: Expediting High Reaction Speed and Preparative Convenience
    Open this publication in new window or tab >>Microwave-Assisted Enantioselective Heck Reactions: Expediting High Reaction Speed and Preparative Convenience
    2002 (English)In: Synthesis, no 11, p. 1611-1614Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90946 (URN)
    Available from: 2003-10-27 Created: 2003-10-27 Last updated: 2013-07-04Bibliographically approved
    4. Arylboronic acids as versatile coupling partners in fast microwave promoted oxidative Heck chemistry
    Open this publication in new window or tab >>Arylboronic acids as versatile coupling partners in fast microwave promoted oxidative Heck chemistry
    2003 (English)In: Molecular diversity, ISSN 1381-1991, E-ISSN 1573-501X, Vol. 7, no 2-4, p. 97-106Article in journal (Refereed) Published
    Abstract [en]

    The useful and selective reactivity of arylboronic acids makes them favourite building blocks for many modern organic chemistry applications like the metal-mediated formation of C-C, C-O, C-N, and C-S bonds. This report describes oxidative Heck coupling reactions of arylboronic acids and olefins, which were conveniently and rapidly (5-30 min) carried out under air with temperature-controlled microwave heating. Different reaction conditions were investigated with regard to both microwave heating capability and chemical productivity. Copper(II) acetate was identified as a microwave compatible reoxidant of Pd(0). The scope and limitations of this high-speed chemistry protocol with diverse olefins and organoboronic acids are discussed.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90947 (URN)10.1023/B:MODI.0000006803.99656.8c (DOI)14870838 (PubMedID)
    Available from: 2003-10-27 Created: 2003-10-27 Last updated: 2017-12-14Bibliographically approved
    5. Microwave-assisted high-speed PCR
    Open this publication in new window or tab >>Microwave-assisted high-speed PCR
    2003 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, Vol. 18, p. 129-132Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90948 (URN)
    Available from: 2003-10-27 Created: 2003-10-27 Last updated: 2013-07-04Bibliographically approved
  • 204.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene.

    In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

    List of papers
    1. Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
    Open this publication in new window or tab >>Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides
    2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 24, p. 11393-11398Article in journal (Refereed) Published
    Abstract [en]

    A bridged two-vial system aminocarbonylation protocol where Mo(CO)(6) functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO)(6)-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 °C reaction temperatures.

    National Category
    Medicinal Chemistry Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-189519 (URN)10.1021/jo302322w (DOI)000312564900046 ()23205569 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Research Council
    Available from: 2013-01-02 Created: 2013-01-02 Last updated: 2018-01-11Bibliographically approved
    2. Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
    Open this publication in new window or tab >>Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide
    2013 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, no 50, p. 6912-6915Article in journal (Refereed) Published
    Abstract [en]

    A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-212521 (URN)10.1016/j.tetlet.2013.10.040 (DOI)000327285300028 ()
    Available from: 2013-12-11 Created: 2013-12-11 Last updated: 2017-12-06Bibliographically approved
    3. Pd-mediated Carbonylative Synthesis of 11C-N-Cyanobenzamides
    Open this publication in new window or tab >>Pd-mediated Carbonylative Synthesis of 11C-N-Cyanobenzamides
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-213862 (URN)
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2014-02-06
    4. 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
    5. 11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
    Open this publication in new window or tab >>11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo
    Show others...
    2014 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, p. 536-543Article in journal (Refereed) Published
    Abstract [en]

    Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

    National Category
    Organic Chemistry Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-213860 (URN)10.1016/j.nucmedbio.2014.03.024 (DOI)000336946400014 ()
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2018-01-11Bibliographically approved
    6. 11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein Aggregates
    Open this publication in new window or tab >>11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein Aggregates
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cardiac and Cardiovascular Systems Surgery Medicinal Chemistry Organic Chemistry
    Research subject
    Medicinal Chemistry; Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-213861 (URN)
    Available from: 2014-01-05 Created: 2014-01-05 Last updated: 2018-01-11
  • 205.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Chow, Shiao Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, A. F.
    Univ Leeds, St James Univ Hosp, England.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-mediated C-11-carbonylations using aryl halides and cyanamide2017In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 22, p. 4875-4881Article in journal (Refereed)
    Abstract [en]

    A robust and high-yielding radiochemical synthesis of C-11-N-cyanobenzamides using a palladium-mediated aminocarbonylation with C-11-CO, aryl halides and cyanamide is described. The bidentate ligand 1,1'-bis(diphenylphosphino)ferrocene provided C-11-N-cyanobenzamides from aryl-iodides, bromides, triflates and even chlorides in 28-79% radiochemical yield after semi-preparative HPLC. To further highlight the utility of this method, novel C-11-N-cyanobenzamide analogs of flufenamic acid, meflanamic acid, dazoxiben and tamibarotene were synthesized in 34-71% radiochemical yields.

  • 206.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Odell, Luke
    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, Organic Pharmaceutical Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    C-11-Labeling of a potent hydroxyethylamine BACE-1 inhibitor and evaluation in vitro and in vivo2014In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, p. 536-543Article in journal (Refereed)
    Abstract [en]

    Introduction

    The enzyme β-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-β, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo.

    Methods

    11[C]-N1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethyl-sulfonamido)-N3-((R)-1-phenylethyl)isophthalamide, a β-secretase inhibitor, denoted here as [11C]BSI-IV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [11C]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats.

    Results

    The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21–26%. [11C]BSI-IV was obtained in 29 ± 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 ± 155 GBq/μmol at the end of synthesis with a radiochemical purity of > 99%. The preclinical studies showed that [11C]BSI-IV has a rapid metabolism in rat with excretion to the small intestines.

    Conclusion

    11[C]BSI-IV was obtained in sufficient amount and purity to enable preclinical investigation. The preclinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [11C]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

  • 207.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Odell, Luke R
    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, Organic Pharmaceutical Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo2014In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, p. 536-543Article in journal (Refereed)
    Abstract [en]

    Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

  • 208.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Friis, Stig D.
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Carbon Dioxide Activat Ctr CADIAC, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, DK-8000 Aarhus C, Denmark..
    Andersen, Thomas L.
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Carbon Dioxide Activat Ctr CADIAC, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, DK-8000 Aarhus C, Denmark..
    Audrain, Helene
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Carbon Dioxide Activat Ctr CADIAC, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, DK-8000 Aarhus C, Denmark..
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Skrydstrup, Troels
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, Carbon Dioxide Activat Ctr CADIAC, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, DK-8000 Aarhus C, Denmark..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Rapid and Efficient Conversion of (CO2)-C-11 to (CO)-C-11 through Silacarboxylic Acids: Applications in Pd-Mediated Carbonylations2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 49, p. 17601-17604Article in journal (Refereed)
    Abstract [en]

    Herein, we present a new rapid, efficient, and low-cost radiosynthetic protocol for the conversion of (CO2)-C-11 to (CO)-C-11 and its subsequent application in Pd-mediated reactions of importance for PET applications. This room-temperature methodology, using readily available chemical reagents, is carried out in simple glass vials, thus eliminating the need for expensive and specialized high-temperature equipment to access (CO)-C-11. With this fast and near-quantitative conversion of (CO2)-C-11 into (CO)-C-11, aryl and heteroaryl iodides were easily converted into a broad selection of biologically active amides in radiochemical yields ranging from 29-84 %.

  • 209.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Johansson, Leif B G
    Department of Chemistry, IFM, Linköping University.
    Bäck, Marcus
    Department of Chemistry, IFM, Linköping University.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hall, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Westermark, Gunilla T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Lars
    Department of Pharmacology, University of Oslo.
    Hammarström, Per
    Department of Chemistry, IFM, Linköping University.
    Nilsson, Peter R
    Department of Chemistry, IFM, Linköping University.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    11C and 18F Radiolabeling of Tetra and Pentathiophenes as PET-Ligands for Misfolded Protein AggregatesManuscript (preprint) (Other academic)
  • 210.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R
    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, Organic Pharmaceutical Chemistry.
    Aminocarbonylations Employing Mo(CO)(6) and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides2012In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 24, p. 11393-11398Article in journal (Refereed)
    Abstract [en]

    A bridged two-vial system aminocarbonylation protocol where Mo(CO)(6) functions as an external in situ solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo(CO)(6)-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65-85 °C reaction temperatures.

  • 211.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Yngve, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilking, Helena
    Gustavsson, Sven Åke
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS)2018In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 61, no 14, p. 1106-1109Article in journal (Refereed)
    Abstract [en]

    The radiosynthesis and GMP validation of [11 C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [11 C]CO2 ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.

  • 212.
    Nordqvist, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hit Identification and Hit Expansion in Antituberculosis Drug Discovery: Design and Synthesis of Glutamine Synthetase and 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Inhibitors2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the discovery of Mycobacterium tuberculosis (Mtb) as the bacterial agent causing tuberculosis, the permanent eradication of this disease has proven challenging. Although a number of drugs exist for the treatment of tuberculosis, 1.7 million people still die every year from this infection. The current treatment regimen involves lengthy combination therapy with four different drugs in an effort to combat the development of resistance. However, multidrug-resistant and extensively drug-resistant strains are emerging in all parts of the world. Therefore, new drugs effective in the treatment of tuberculosis are much-needed.

    The work presented in this thesis was focused on the early stages of drug discovery by applying different hit identification and hit expansion strategies in the exploration of two new potential drug targets, glutamine synthetase (GS) and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR).

    A literature survey was first carried out to identify new Mtb GS inhibitors from compounds known to inhibit GS in other species. Three compounds, structurally unrelated to the typical amino acid derivatives of previously known GS inhibitors, were then discovered by virtual screening and found to be Mtb GS inhibitors, exhibiting activities in the millimolar range. Imidazo[1,2-a]pyridine analogues were also investigated as Mtb GS inhibitors. The chemical functionality, size requirements and position of the substituents in the imidazo[1,2-a]pyridine hit were investigated, and a chemical library was designed based on a focused hierarchical design of experiments approach. The X-ray structure of one of the inhibitors in complex with Mtb GS provided additional insight into the structure–activity relationships of this class of compounds.

    Finally, new α-arylated fosmidomycin analogues were synthesized as inhibitors of Mtb DXR, exhibiting IC50 values down to 0.8 µM. This work shows that a wide variety of aryl groups are tolerated by the enzyme. Cinnamaldehydes are important synthetic intermediates in the synthesis of fosmidomycin analogues. These were prepared by an oxidative Heck reaction from acrolein and various arylboronic acids. Electron-rich, electron-poor, heterocyclic and sterically hindered boronic acids could be employed, furnishing cinnamaldehydes in 43–92% yield.

    List of papers
    1. Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery
    Open this publication in new window or tab >>Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery
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    2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 10, p. 5501-5513Article in journal (Refereed) Published
    Abstract [en]

    A combination of a literature survey, structure-based virtual screening and synthesis of a small library was performed to identify hits to the potential antimycobacterial drug target, glutamine synthetase. The best inhibitor identified from the literature survey was (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid (4, IC(50) of 610+/-15microM). In the virtual screening 46,400 compounds were docked and subjected to a pharmacophore search. Of these compounds, 29 were purchased and tested in a biological assay, allowing three novel inhibitors containing an aromatic scaffold to be identified. Based on one of the hits from the virtual screening a small library of 15 analogues was synthesized producing four compounds that inhibited glutamine synthetase.

    Keywords
    virtual screening, glutamine synthetase, gamma-glutamyl, ammonia ligase
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102946 (URN)10.1016/j.bmc.2008.04.015 (DOI)000256052400015 ()18462943 (PubMedID)
    Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2018-01-13Bibliographically approved
    2. Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
    Open this publication in new window or tab >>Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
    Show others...
    2007 (English)In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 10, no 9, p. 783-789Article in journal (Refereed) Published
    Abstract [en]

    A microwave-enhanced, palladium-catalyzed protocol for the alpha-arylation of a protected glycine in neat water is described. This reaction proceeds rapidly, under non-inert conditions, to afford a range of phenylglycine derivatives in moderate to good yields. Based on this arylation, a number of aryl L-methionine-SR-sulfoximine (MSO) analogues were prepared and evaluated for their Mycobacterium tuberculosis glutamine synthetase (TB-GS) inhibitory activity.

    Keywords
    arylation, glutamine synthetase, microwave, palladium, tuberculosis, water
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-16614 (URN)10.2174/138620707783018478 (DOI)000253584600005 ()18478959 (PubMedID)
    Available from: 2008-06-05 Created: 2008-06-05 Last updated: 2018-01-12Bibliographically approved
    3. Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
    Open this publication in new window or tab >>Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
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    2009 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, no 16, p. 4790-4793Article in journal (Refereed) Published
    Abstract [en]

    3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC50 = 0.38 ± 0.02 μM). This compound was significantly more potent than the known inhibitors, L-methionine-SR-sulfoximine and phosphinothricin.

    Keywords
    Mycobacterium tuberculosis, Glutamine synthetase inhibitors, Microwave, 3-Aminoimidazo[1, 2-a]pyridine
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-100360 (URN)10.1016/j.bmcl.2009.06.045 (DOI)000268358800057 ()19560924 (PubMedID)
    Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2018-01-13Bibliographically approved
    4. Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
    Open this publication in new window or tab >>Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
    Show others...
    2012 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 3, no 5, p. 620-626Article in journal (Refereed) Published
    Abstract [en]

    Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.

    National Category
    Medicinal Chemistry Medical and Health Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-100359 (URN)10.1039/c2md00310d (DOI)000304387300013 ()
    Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2018-01-13Bibliographically approved
    5. Synthesis of Functionalized Cinnamaldehyde Derivatives by an Oxidative Heck Reaction and Their Use as Starting Materials for Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Inhibitors
    Open this publication in new window or tab >>Synthesis of Functionalized Cinnamaldehyde Derivatives by an Oxidative Heck Reaction and Their Use as Starting Materials for Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Inhibitors
    Show others...
    2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 21, p. 8986-8998Article in journal (Refereed) Published
    Abstract [en]

    Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, base-free palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,β-unsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate reductoisomerase. IC(50) values between 0.8 and 27.3 μM were measured. The best compound showed activity comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.

    National Category
    Natural Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-158249 (URN)10.1021/jo201715x (DOI)000296206400040 ()21936546 (PubMedID)
    Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
  • 213.
    Nordqvist, Anneli
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nilsson, Mikael T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Lagerlund, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Muthas, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Yahiaoui, Samir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Srinivasa, Bachally R.
    Astra Research Center India, Bangalore, India.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mowbray, Sherry L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors2012In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 3, no 5, p. 620-626Article in journal (Refereed)
    Abstract [en]

    Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.

  • 214.
    Nordström, Randi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Saunders, Brian
    Univ Manchester, Manchester, Lancs, England.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Responsive nanogels as carriers for antimicrobial peptides2017In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 253Article in journal (Other academic)
  • 215. Nordvall, Gunnar
    et al.
    Yngve, Ulrika.
    Preparation of piperazinyl quinazolines as 5-HT6 modulators.2007Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl, (hetero)cycloalkylalkyl or alkyl; B = CH or N; R1 = H, OH, halo, alkyl, etc.; R2 = H, (halo)alkyl, aminocarbonylalkyl, etc.; R3 = H, (halo)alkyl or alkylaryl; R4 = CN, halo, alkoxy, etc.; m = 0-2; n = 0-4; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2,4-dichloroquinazoline with benzenesulfonamide and followed by reaction with N-methylpiperazine, gave N-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]benzenesulfonamide in 6% yield. The radioligand binding assay showed II having Ki of 1.4 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]

  • 216. Nordvall, Gunnar
    et al.
    Yngve, Ulrika.
    Preparation of piperazinyl quinazolines as 5-HT6 modulators.2007Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl; R1 = OH, halo, alkyl, etc.; R2, R3 = independently H, (halo)alkyl, aminocarbonylalkyl, etc.; n = 0-3; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2-chloro-4-(4-methylpiperazin-1-yl)quinazoline with N-methyl-4-chlorobenzenesulfonamide gave II in 10% yield. The radioligand binding assay showed II having Ki of 200 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]

  • 217.
    Nurbo, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Peptidomimetic Enzyme Inhibitors: Targeting M. tuberculosis Ribonucleotide Reductase and Hepatitis C Virus NS3 Protease2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on the design and synthesis of inhibitors targeting Mycobacterium tuberculosis ribonucleotide reductase (RNR) and hepatitis C virus (HCV) NS3 protease; enzymes that have been identified as potential drug targets for the treatment of tuberculosis and hepatitis C, respectively. Small peptides have been recognized as inhibitors of these enzymes. However, the use of peptides as drugs is limited due to their unfavorable properties. These can be circumvented by the development of less peptidic molecules, often referred to as peptidomimetics. When this work was initiated, only a few inhibitors targeting M. tuberculosis RNR had been identified, whereas the HCV NS3 protease was an established drug target. Therefore, early peptidomimetic design strategies were applied to inhibitors of RNR while the NS3 protease inhibitors were subjected to modifications in a later stage of development.

    It has previously been shown that peptides derived from the C-terminus of the small subunit of M. tuberculosis RNR can compete for binding to the large subunit, and thus inhibit enzyme activity. To investigate the structural requirements of these inhibitors, different series of peptides were evaluated. First, peptides from an N-terminal truncation, an alanine scan and a designed library were synthesized and evaluated to examine the importance of the individual amino acid residues. Then, a set of N-terminally Fmoc-protected peptides was evaluated, and it was found that the N-terminal group improved the affinity of the peptides even when the length of the compounds was reduced. Furthermore, potential inhibitors of less peptidic character were generated by the introduction of a benzodiazepine-based scaffold.

    To further reduce the peptidic character and investigate the binding properties of HCV NS3 protease inhibitors, a series of tripeptides incorporating a β-amino acid was synthesized. Inhibition was evaluated and docking studies were performed to understand how the structural changes affected inhibitory potency. The results illustrated the importance of preserving the hydrogen bonding network and retaining electrostatic interactions in the oxyanion hole between inhibitor and protein.

    List of papers
    1. Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
    Open this publication in new window or tab >>Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
    Show others...
    2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 12, p. 822-832Article in journal (Refereed) Published
    Abstract [en]

    Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that TrP5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain., as compared to Trp5.

    Keywords
    mycobacterium tuberculosis, ribonucleotide reductase, peptide inhibitors, alanine scan, statistical molecular design, structure activity relationships, FHDoE
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-14261 (URN)10.1002/psc.906 (DOI)000252000600007 ()17918768 (PubMedID)
    Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
    2. Identification of small peptides mimicking the R2 C-terminus of Mycobacterium tuberculosis ribonucleotide reductase
    Open this publication in new window or tab >>Identification of small peptides mimicking the R2 C-terminus of Mycobacterium tuberculosis ribonucleotide reductase
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    2010 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 16, no 3, p. 159-164Article in journal (Refereed) Published
    Abstract [en]

    Ribonucleotide reductase (RNR) is a viable target for new drugs against the causative agent of tuberculosis, Mycobacterium tuberculosis. Previous work has shown that an N-acetylated heptapeptide based on the C-terminal sequence of the smaller RNR subunit can disrupt the formation of the holoenzyme sufficiently to inhibit its function. Here the synthesis and binding affinity, evaluated by competitive fluorescence polarization, of several truncated and N-protected peptides are described. The protected single-amino acid Fmoc-Trp shows binding affinity comparable to the N-acetylated heptapeptide, making it an attractive candidate for further development of non-peptidic RNR inhibitors.

    Keywords
    Fluorescence polarization, Mycobacterium tuberculosis, Peptide inhibitors, Ribonucleotide reductase
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-112344 (URN)10.1002/psc.1214 (DOI)000275448300007 ()20127854 (PubMedID)
    Available from: 2010-01-26 Created: 2010-01-13 Last updated: 2018-01-12Bibliographically approved
    3. Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic – targeting Mycobacterium tuberculosis ribonucleotide reductase
    Open this publication in new window or tab >>Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic – targeting Mycobacterium tuberculosis ribonucleotide reductase
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    2013 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 21, no 7, p. 1992-2000Article in journal (Refereed) Published
    Abstract [en]

    Peptides mimicking the C-terminus of the small subunit (R2) of Mycobacterium tuberculosis ribonucleotide reductase (RNR) can compete for binding to the large subunit (R1) and thus inhibit RNR activity. Moreover, it has been suggested that the binding of the R2 C-terminus is very similar in M. tuberculosis and Salmonella typhimurium. Based on modeling studies of a crystal structure of the holocomplex of the S. typhimurium enzyme, a benzodiazepine-based turn mimetic was identified and a set of novel compounds incorporating the benzodiazepine scaffold was synthesized. The compounds were evaluated in a competitive fluorescence polarization assay and in an RNR activity assay. These studies revealed that the compounds incorporating the benzodiazepine scaffold have the ability to compete for the M. tuberculosis R2 binding site with low-micromolar affinity.

    National Category
    Biological Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-112341 (URN)10.1016/j.bmc.2013.01.020 (DOI)000316770300041 ()
    Available from: 2010-01-26 Created: 2010-01-13 Last updated: 2017-12-12Bibliographically approved
    4. β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
    Open this publication in new window or tab >>β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors
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    2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 10, p. 5590-5605Article in journal (Refereed) Published
    Abstract [en]

    In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of alpha- and beta-amino acids has been synthesized. To understand the structural implications of beta-amino acid substitution, the P(1), P(2), and P(3) positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the alpha-peptide analogues. However, several compounds exhibited muM potency. Inhibition data were compared with modeled ligand-protein binding poses to understand how changes in ligand structure affected inhibition potency. The P(3) position seemed to be the least sensitive position for beta-amino acid substitution. Moreover, the importance of a proper oxyanion hole interaction for good potency was suggested by both inhibition data and molecular modeling. To gain further insight into the structural requirements for potent inhibitors, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model has been constructed using comparative molecular field analysis (CoMFA). The most predictive CoMFA model has q(2)=0.48 and r(pred)(2)=0.68.

    Keywords
    hepatitis C, HCV, NS3, protease inhibitor, beta-amino acid, 3D-QSAR, CoMFA, docking
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96053 (URN)10.1016/j.bmc.2008.04.005 (DOI)000256052400023 ()18434166 (PubMedID)
    Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2018-01-13Bibliographically approved
  • 218.
    Nöteberg, Daniel
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Design and synthesis of aspartyl protease inhibitors: Targeting HIV-1 and malaria plasmepsin I and II2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Aspartyl proteases can generally be inhibited by peptide mimics containing an uncleavable peptide bond isostere at the proposed cleavage site. One such peptide bond isostere is the hydroxyethylamine moiety, which in this thesis has successfully been incorporated in potential inhibitors of the HIV-1-protease as well as the malarial proteases plasmepsin I and II.

    The human immunodeficiency virus (HIV) has during the last 20 years given rise to a new fast-spread epidemic. The virus protease is one of the foremost targets for drug intervention. In an attempt to improve an earlier design, a P1'-anthranilic acid was exchanged for all four isomers of 2-aminocyclopentanecarboxylic acid, which were synthesized from racemic starting materials, the trans isomers via a novel synthetic route. None of the isomers enhanced potency as compared to the anthranilic acid.

    Because of increasing development of resistance, the pharmaceutical intervention with malaria is becoming rapidly more difficult. A prominent new target for drug research is the hemoglobin degradation pathway. Two of the many proteases involved in this pathway are plasmepsin I and II. Two series of peptide mimics with the hydroxyethylamine were prepared and tested against these enzymes as well as against the similar human protease cathepsin D.

    In the first series the central nitrogen of the target compounds is a secondary amine, derived from natural and unnatural amino acids, the side-chain of which was to bind in the S1'-site of the proteases. It was found that para-aryl substituted phenylalanines resulted in the most active inhibitors. While the P1- and P2-side-chains were kept constant at benzyl and isopropyl respectively, the P3 capping carboxylic acid was varied with a set of diverse carboxylic acids. It was found that many of the carboxylic acids were acceptable.

    A selection of compounds was tested for inhibition of parasite growth in infected human erythrocytes and found to be active.

    In the target compounds of the second series the P1'-side-chain was moved from the α-carbon of the initial amino acids to the adjacent nitrogen, thus rendering this a tertiary amine. The SAR of these compounds suggests that this side-chain cannot be larger than benzyl, which is in sharp contrast to the first series, where both isomers of phenylalanine (i.e. a benzyl group on the α-carbon) render inactive compounds.

    Most of the compounds show a good degree of selectivity for the plasmepsins over cathepsin D, even though a few good inhibitors of the human enzyme could be identified also.

  • 219.
    Nöteberg, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hamelink, Elizabeth
    Vrang, Lotta
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    High-speed optimization of inhibitors of the malarial proteases plasmepsin I and II2003In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 5, no 4, p. 456-464Article in journal (Refereed)
    Abstract [en]

    Four focused libraries targeted for inhibition of the malarial proteases plasmepsin I and II were designed, synthesized, purified, and screened. Selected carboxylic acids and organometallic reactants with diverse physical properties were attached to the hydroxylethylamine scaffold in the P3 and P1‘ positions to furnish inhibitors with highly improved activity. The concept of controlled and sequential microwave heating was employed for rapid library generation. This combinatorial optimization protocol afforded plasmepsin inhibitors not only with Ki values in the low nanomolar range, but also with high selectivity versus the human protease cathepsin D. With this class of inhibitory agents, modifications of the P1‘ substituents resulted in the largest impact on the plasmepsin/cathepsin D selectivity.

  • 220.
    Odell, Luke R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
    Abdel-Hamid, Mohammed K.
    Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia.;Assiut Univ, Fac Pharm, Dept Med Chem, Assiut 71526, Egypt..
    Hill, Timothy A.
    Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
    Chau, Ngoc
    Young, Kelly A.
    Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
    Deane, Fiona M.
    Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
    Sakoff, Jennette A.
    Calvary Mater Newcastle Hosp, Dept Med Oncol, Expt Therapeut Grp, Edith St, Waratah, NSW 2298, Australia..
    Andersson, Sofia
    Malardalens Univ, Dept Biol & Chem Engn, Box 325, S-63105 Eskilstuna, Sweden..
    Daniel, James A.
    Univ Sydney, Childrens Med Res Inst, 214 Hawkesbury Rd, Westmead, NSW 2145, Australia.;Max Planck Inst Expt Med, Mol Neurobiol Grp, Hermann Rein Str 3, D-37075 Gottingen, Germany..
    Robinson, Phillip J.
    Univ Sydney, Childrens Med Res Inst, 214 Hawkesbury Rd, Westmead, NSW 2145, Australia..
    McCluskey, Adam
    Univ Newcastle, Sch Environm & Life Sci, Chem, Callaghan, NSW 2308, Australia..
    Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 1, p. 349-361Article in journal (Refereed)
    Abstract [en]

    The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds, were reported to disrupt clynamin localization to the plasina membrane via the PH domain and,iniplicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 +/- 1.3 to 1.6 +/- 0.3 mu M) and CME (IC50(CME) = 65.9 +/- 7.7 to 17 +/- 1.1 mM), which makes this. series among The more potent inhibitors of dynamin.and CME yet reported. In:CME and growth inhibition cell-based assays, the data obtained Was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-.target effects at the cholecystokinin, dopamine D-2, histamine H-1 and H-2, melanocortin, rnelatonin, muscarir* M-1 and M-3 neurokinin, opioid KOP and serotonin receptors.

  • 221.
    Odell, Luke R
    et al.
    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, Organic Pharmaceutical Chemistry.
    Microwave-Assisted Transition Metal-Catalyzed Asymmetric Synthesis2011In: Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications / [ed] Michelangelo Gruttadauria, Francesco Giacalone, Oxford: Wiley-Blackwell, 2011, p. 391-412Chapter in book (Refereed)
  • 222.
    Odell, Luke R
    et al.
    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, Organic Pharmaceutical Chemistry.
    Richard F. Heck: Nobel Laureate in Chemistry2011In: Les Prix Nobel, ISSN 0546-8175, p. 133-138Article in journal (Refereed)
  • 223.
    Odell, Luke R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Russo, Francesco
    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, Organic Pharmaceutical Chemistry.
    Molybdenum Hexacarbonyl Mediated CO Gas-Free Carbonylative Reactions2012In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, no 5, p. 685-698Article in journal (Refereed)
    Abstract [en]

    This Account summarizes predominately our own experiences in developing microwave-heated palladium-catalyzed Mo(CO)6-mediated gas-free carbonylative reactions, although contributions from other groups, including non-palladium-catalyzed examples, have also been covered. Presented reactions include amino-, amido-, and alkoxycarbonylations as well as carbonylative cyclizations and carbonylative cross-couplings, using Mo(CO)6 as a solid source of CO. The methodology was developed mainly for rapid small-scale applications, avoiding the problematic use of gaseous CO in a standard laboratory. In most cases, the reported Mo(CO)6-mediated carbonylations were conducted in sealed vessels and with reaction times of less than 1 hour. The Account also highlights relevant applications in medicinal and high-speed chemistry.

  • 224. Ohsawa, Masahiro
    et al.
    Carlsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Asato, Megumi
    Koizumi, Takayuki
    Nakanishi, Yuki
    Fransson, Rebecca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kamei, Junzo
    The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system2011In: Molecular Pain, ISSN 1744-8069, Vol. 7, p. 85-Article in journal (Refereed)
    Abstract [en]

    Background: Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P1-7 (SP1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP1-7 and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice. Results: Intrathecal treatment with the dipeptide increased the tail-flick latency in both diabetic and non-diabetic mice. This effect of Phe-Phe amide was significantly greater in diabetic mice than non-diabetic mice. The Phe-Phe amide-induced antinociceptive effect in both diabetic and non-diabetic mice was reversed by the σ1 receptor agonist (+)-pentazocine. Moreover, Phe-Phe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)-pentazocine. The expression of spinal σ1 receptor mRNA and protein did not differ between diabetic mice and non-diabetic mice. On the other hand, the expression of phosphorylated extracellular signal-regulated protein kinase 1 (ERK1) and ERK2 proteins was enhanced in diabetic mice. (+)-Pentazocine caused phosphorylation of ERK1 and ERK2 proteins in non-diabetic mice, but not in diabetic mice. Conclusions: These results suggest that the spinal σ1 receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.

  • 225.
    Olofsson, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Regiocontrol in the Heck-reaction and fast fluorous chemistry2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The palladium-catalysed Heck-reaction has been utilised in organic synthesis, where the introduction of aryl groups at the internal, β-carbon of different allylic substrates has been achieved with high regioselectivity.

    The β-stabilising effect of silicon enhances the regiocontrol in the internal arylation of allyltrimethylsilane, while a coordination between palladium and nitrogen induces very high regioselectivities in the arylation of N,N-dialkylallylamines and the Boc-protected allylamine, producing β-arylated arylethylamines, which are of interest for applications in medicinal chemistry. Phthalimido-protected allylamines are arylated with poor to moderate regioselectivity.

    Single-mode microwave heating can reduce the reaction times of Heck-, Stille- and radical mediated reactions drastically from approximately 20 hours to a few minutes with, in the majority of cases, retained, high regioselectivity.

    The use of heavily fluorinated tin reagents, which proved to be unreactive under thermal heating, is shown to be applicable with microwave-heating and the high fluorous content of the products is utilised with the aim of improving and simplifying the work-up procedure.

  • 226.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hofström, Camilla
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gräslund, Torbjörn
    [99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Purpose

    Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule 111In-DOTA-His6-ZIGF1R:4551. The use of 99mTc instead of 111In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His6 tag in ZIGF1R:4551 would permit its convenient purification using IMAC, enable labelling with [99mTc(CO)3]+, and improve its biodistribution.

    Methods

    ZIGF1R:4551 was expressed with a HEHEHE tag in the N terminus. The resulting (HE)3-ZIGF1R:4551 construct was labelled with [99mTc(CO)3]+. Targeting of IGF-1R-expressing cells using [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 was evaluated in vitro and in vivo.

    Results

    (HE)3-ZIGF1R:4551 was stably labelled with 99mTc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 demonstrated 3.6-fold lower accumulation in the liver and spleen than 111In-DOTA-ZIGF1R:4551. In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 ± 0.11 %ID/g and the tumour-to-blood ratio was 4.4 ± 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection.

    Conclusion

    99mTc(CO)3]+-(HE)3-ZIGF1R:4551 is a promising candidate for visualization of IGF-1R expression in malignant tumours.

  • 227.
    Oroujeni, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Andersson, Ken G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Steinhardt, Xenia
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Löfblom, John
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules2018In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 50, no 8, p. 981-994Article in journal (Refereed)
    Abstract [en]

    Epidermal growth factor receptor (EGFR) is overexpressed in a number of cancers and is the molecular target for several anti-cancer therapeutics. Radionuclide molecular imaging of EGFR expression should enable personalization of anti-cancer treatment. Affibody molecule is a promising type of high-affinity imaging probes based on a non-immunoglobulin scaffold. A series of derivatives of the anti-EGFR affibody molecule ZEGFR:2377, having peptide-based cysteine-containing chelators for conjugation of Tc-99m, was designed and evaluated. It was found that glutamate-containing chelators Gly-Gly-Glu-Cys (GGEC), Gly-Glu-Glu-Cys (GEEC) and Glu-Glu-Glu-Cys (EEEC) provide the best labeling stability. The glutamate containing conjugates bound to EGFR-expressing cells specifically and with high affinity. Specific targeting of EGFR-expressing xenografts in mice was demonstrated. The number of glutamate residues in the chelator had strong influence on biodistribution of radiolabeled affibody molecules. Increase of glutamate content was associated with lower uptake in normal tissues. The Tc-99m-labeled variant containing the EEEC chelator provided the highest tumor-to-organ ratios. In conclusion, optimizing the composition of peptide-based chelators enhances contrast of imaging of EGFR-expression using affibody molecules.

  • 228.
    Orrling, Kristina M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    On the Versatility of Microwave-Assisted Chemistry: Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today, the demand for speed in drug discovery is constantly increasing, particularly in the iterative processes of hit validation and expansion and lead optimization. Irradiation with microwaves (MWs) has been applied in the area of organic synthesis to accelerate chemical reactions and to facilitate the generation of new chemical entities since 1986. In the work presented in this thesis, the use of MW-mediated heating has been expanded to address three fields of drug discovery, namely hit expansion, chemical library generation and genomics.

    In the first project, potential inhibitors of malaria aspartic proteases were designed and synthesized, partly by MW-assisted organic chemistry, and evaluated with regard to their inhibitory efficacy on five malaria aspartic proteases and their selectivity over two human aspartic proteases. The synthetic work included the development of fast and convenient methods of MW-assisted formation of thiazolidines and epoxy esters. Some of the resulting structures proved to be efficacious inhibitors of the aspartic protease that degrades haemoglobin in all four malaria parasites infecting man. No inhibitor affected the human aspartic proteases.

    Expedient, two-step, single-operation synthetic routes to heterocycles of medicinal interest were developed in the second and third projects. In the former, the use of a versatile synthon, Ph3PCCO, provided α,β-unsaturated lactones, lactams and amides within 5–10 minutes. In the latter project, saturated lactams were formed from amines and lactones in 35 minutes, in the absence of strong additives. These two MW-mediated protocols allowed the reduction of the reaction time from several hours or days to minutes.

    In the fourth project, a fully automated MW-assisted protocol for the important enzyme-catalysed polymerase chain reaction (PCR) was established. In addition, the PCR reaction could be performed in unusually large volumes, 2.5 mL and 15 mL, with yields corresponding to those from conventional PCR. Good amplification rates suggested that the thermophilic enzyme, Taq polymerase, was not affected by the MW radiation.

    List of papers
    1. α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
    Open this publication in new window or tab >>α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
    Show others...
    2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 16, p. 5933-5949Article in journal (Refereed) Published
    Abstract [en]

    The impact of moving the P1 side-chain from the β-position to the α-position in norstatine-containing plasmepsin inhibitors was investigated, generating two new classes of tertiary alcohol-comprising α-benzylnorstatines and α-phenylnorstatines. Twelve α-substituted norstatines were designed, synthesized and evaluated for their inhibitory potencies against plasmepsin II and the plasmepsin IV orthologues (PM4) present in the digestive vacuole of all four Plasmodium species causing malaria in man. New synthetic routes were developed for producing the desired α-substituted norstatines as pure stereoisomers. The best compounds provided Ki values in the nanomolar range for all PM4, with a best value of 110 nm in PM4 from P. ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to P. falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor–protein binding affinities using the linear interaction energy method (LIE).

    Keywords
    malaria, plasmepsin, inhibitors, microwave-assisted synthesis, molecular dynamics, Linear interaction energy mehtod
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-100961 (URN)10.1016/j.bmc.2009.06.065 (DOI)000268762900020 ()
    Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2018-01-13Bibliographically approved
    2. Cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating
    Open this publication in new window or tab >>Cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating
    2002 (English)In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 5, no 7, p. 571-574Article in journal (Refereed) Published
    Abstract [en]

    A general procedure for the synthesis of a large variety of compounds comprising an alpha, beta-unsaturated carbonyl functionality was developed. The use of one-pot cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for various formations including heterocycles of different ring sizes and unsaturated amides in combination with microwave dielectric heating is described. The method was used to synthesize a small library of unsaturated amides.

    Keywords
    microwave heating, one-pot synthesis, cascade reaction, library synthesis, (triphenylphosphoranylidene)ethenone, organic-synthesis, cumulated ylides, chemistry
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-100964 (URN)000181710400008 ()12470270 (PubMedID)1386-2073 (ISBN)
    Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2017-12-13Bibliographically approved
    3.
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    4. An efficient method to perform milliliter-scale PCR utilizing highly controlled microwave thermocycling
    Open this publication in new window or tab >>An efficient method to perform milliliter-scale PCR utilizing highly controlled microwave thermocycling
    2004 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 7, no 7, p. 790-791Article in journal (Refereed) Published
    Abstract [en]

    This communication describes the development of a controlled microwave methodology for rapid milliliter-scale PCR.

    Keywords
    organic-chemistry, DNA, selection, proteins, site
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-100963 (URN)10.1039/b317049g (DOI)15045065 (PubMedID)1359-7345 (ISBN)
    Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2017-12-13Bibliographically approved
  • 229.
    Over, Bjorn
    et al.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden..
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tyrchan, Christian
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Doak, Bradley C.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Foley, Michael A.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Triinst Therapeut Discovery Inst, New York, NY USA..
    Hilgendorf, Constanze
    AstraZeneca R&D Gothenburg, Safety & ADME Translat Sci, Drug Safety & Metab, Molndal, Sweden..
    Johnston, Stephen E.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Lee, Maurice D.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Lewis, Richard J.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    McCarren, Patrick
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Muncipinto, Giovanni
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Norinder, Ulf
    Swedish Toxicol Sci Res Ctr, Sodertalje, Sweden..
    Perry, Matthew W. D.
    Duvall, Jeremy R.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Structural and conformational determinants of macrocycle cell permeability2016In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, p. 1065-+Article in journal (Refereed)
    Abstract [en]

    Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

  • 230.
    Pelcman, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sanin, Andrei
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    No, Kiyo
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Öhrman, Sara
    Krog-Jensen, Christian
    Forsell, Pontus
    Hallberg, Anders
    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, Organic Pharmaceutical Chemistry.
    Boesen, Thomas
    Kromann, Hasse
    Vogensen, Stine Byskov
    Groth, Thomas
    Claesson, Hans-Erik
    3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15-lipoxygenase-12015In: Bioorganic & medicinal chemistry letters, ISSN 1464-3405, Vol. 25, no 15, p. 3024-3029Article in journal (Refereed)
    Abstract [en]

    Investigation of 1N-substituted pyrazole-3-carboxanilides as 15-lipoxygenase-1 (15-LOX-1) inhibitors demonstrated that the 1N-substituent was not essential for activity or selectivity. Additional halogen substituents on the pyrazole ring, however, increased activity. Further development led to triazole-4-carboxanilides and 2-(3-pyrazolyl) benzoxazoles, which are potent and selective 15-LOX-1 inhibitors.

  • 231.
    Pelcman, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sanin, Andrei
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olofsson, Kristofer
    Krog-Jensen, Christian
    Forsell, Pontus
    Hallberg, Anders
    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, Organic Pharmaceutical Chemistry.
    Boesen, Thomas
    Kromann, Hasse
    Claesson, Hans-Erik
    N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase2015In: Bioorganic & medicinal chemistry letters, ISSN 1464-3405, Vol. 25, no 15, p. 3017-3023Article in journal (Refereed)
    Abstract [en]

    High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.

  • 232.
    Perspicace, Enrico
    et al.
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Jouan-Hureaux, Valérie
    EA 4421 SiGReTO, Université de Lorraine, Faculté de pharmacie, 5-7 Rue Albert Lebrun, BP80403, 54001 Nancy cedex, France.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “ La Sapienza ” , P. le A. Moro 5, 00185 Roma, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma “ La Sapienza ” , P. le A. Moro 5, 00185 Roma, Italy.
    Sartini, Stefania
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    La Motta, Concettina
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    Da Settimo, Federico
    Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
    Chen, Binbin
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Kirsch, Gilbert
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Schneider, Serge
    Laboratoire National de Santé, Division de Toxicologie, Université de Luxembourg, 162a Avenue de la Faïencerie, L-1511 Luxembourg, Luxembourg.
    Faivre, Béatrice
    EA 4421 SiGReTO, Université de Lorraine, Faculté de pharmacie, 5-7 Rue Albert Lebrun, BP80403, 54001 Nancy cedex, France.
    Hesse, Stéphanie
    Laboratoire d ’ Ingénierie Moléculaire et Biochimie Pharmacologique, UMR CNRS 7565 SRSMC, Institut Jean Barriol, FR CNRS 2843, Université de Lorraine, 1 Boulevard Arago, 57070 Metz, France.
    Design, synthesis and biological evaluation of new classes of thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2).2013In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 63, p. 765-81, article id S0223-5234(13)00170-0Article in journal (Refereed)
    Abstract [en]

    Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure-Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1-3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level.

  • 233.
    Persson, Anita M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of a Miniaturized Rotating Disk Apparatus for In Vitro Dissolution Rate Measurements in Aqueous Media: Correlation of In Vitro Dissolution Rate with Apparent Solubility2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The general aim of this thesis was to evaluate a newly designed and constructed miniaturized rotating disk apparatus for in vitro dissolution rate measurements of different drug substances from all of the classes in the Biopharmaceutical Classification System (BCS). The new equipment is based on a low volume flow-through cell of Plexiglas, a gold plated magnetic bar and a special designed press. The disk of drug substance (approx. 5 mg) is placed eccentrically in the bar. Rotation speeds were set with a graded magnetic stirrer. An external HPLC pump delivered a continuous flow of aqueous medium to the flow-through cell during dissolution testing.

    A reversed phase high-performance liquid chromatography system using diode array detection (RP-HPLC-DAD) was coupled online to the new equipment. The injections from the miniaturized rotating disk outlet into the quantifying HPLC system were controlled by a six-position switching valve. The injection volumes from the valve and the autosampler, used for the external standards, were statistically evaluated to match each other volumetrically. No analyses were longer than three minutes, using isocratic mode.

    A traditional USP rotating disk apparatus was used as a reference system and the two instruments were shown to be statistically dissimilar in the numerical dissolution rate values probably due to different hydrodynamics, but had approximately the same precision/repeatability. When correlating the logarithmic values of the in vitro dissolution rate (G) with the apparent solubility (S), using shake-flask methodology in the solubility studies, the two apparatuses gave the same correlation patterns. Further correlation studies were done where the media components were altered by the use of different buffer species or additives into the buffers, such as inorganic salts.

    Chemometric tools, e.g. orthogonal partial least squares (OPLS), were used to better evaluate the most influential factors for G and S in different media. The most significant factor for a model basic drug substance (terfenadine) was pH, followed by the ionic strength (I) and added sodium chloride in one of the media. However, the surfactants in the Fasted State Simulated Intestinal Fluid (FaSSIF-V2) were found to be insignificant for G and S in this study (using a 95% confidence interval).

    The new miniaturized apparatus is a promising prototype for in vitro dissolution rate measurements both for early screening purposes and in dissolution testing during drug development, but needs further instrumental improvements.

    List of papers
    1. Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies
    Open this publication in new window or tab >>Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies
    Show others...
    2008 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3344-3355Article in journal (Refereed) Published
    Abstract [en]

    A miniaturized apparatus for the determination of the apparent in vitro dissolution rate has been designed, constructed and characterized. The miniaturized apparatus was based on a low volume dissolution cell and a disk in a rotating magnetic bar. The disk tablet is pressed directly into the bar with a press designed and constructed for this purpose. It requires approximately 5 mg of substance. The disk was positioned eccentrically on the bar with an external flow of medium to increase the rate of solvent flow over the disk surface. Six different drug substances were used. The dissolution media were sodium phosphate buffer, pH 7.0, and ammonium acetate buffer, pH 6.8. All quantifications were made by integrating the dissolution cell with high-performance liquid chromatography (HPLC) using diode-array detection (DAD). The obtained results were compared with data from a conventional rotating disk equipment, where the disk was centrically mounted. The dissolution rates at 100 rpm seemed to be on an average of 2-3 times higher for the miniaturized apparatus (RSD 0.2-56%). The preliminary studies of this prototype indicate that the miniaturized rotating disk is a promising design for the qualitative estimation of dissolution rates of substances, for example during screening in early drug discovery.

    Place, publisher, year, edition, pages
    Wiley InterScience, 2008
    Keywords
    dissolution rate, in vitro models, physicochemical properties; analytical chemistry, HPLC (high-performance/pressure liquid chromatography), miniaturization
    National Category
    Medicinal Chemistry Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-17637 (URN)10.1002/jps.21235 (DOI)000258081100034 ()
    Available from: 2010-01-11 Created: 2009-10-08 Last updated: 2018-01-12Bibliographically approved
    2. Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus
    Open this publication in new window or tab >>Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus
    2009 (English)In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 104-113Article in journal (Refereed) Published
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and the apparent solubility, S, was evaluated in phosphate and ammonium acetate buffer at an initial pH of 7. The dissolution rates were determined with a newly designed and build miniaturized rotating disk equipment, as well as with a traditional rotating disk apparatus. The two apparatuses gave the same correlation pattern of logG and logS. Thirteen diverse drug substances from all of the classes in the Biopharmaceutics Classification System (BCS) were used for the correlation in the phosphate buffer system, with the results from the miniaturized apparatus only. A coefficient of determination, R2, of 0.982 was found if bases formulated as hydrochloride salts were excluded in the correlation. The miniaturized equipment is used for rapid screening of the dissolution rate, approximately 10 min for one run, and consumes small amounts of substance (about 5 mg) and dissolution media. All quantifications were performed by using reversed phase high-performance liquid chromatography (RPHPLC) with a diode array detector (DAD), integrated with the miniaturized rotating disk equipment.

    Place, publisher, year, edition, pages
    IACMHR and SDU-DDSC, 2009
    Keywords
    dissolution rate, solubility, in vitro models, correlation, HPLC (high-performance liquid chromatography)
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-107740 (URN)
    Available from: 2010-01-11 Created: 2009-08-25 Last updated: 2018-01-13Bibliographically approved
    3. Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media
    Open this publication in new window or tab >>Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media
    2009 (English)In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 114-122Article in journal (Refereed) Published
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and apparent solubility, S, was made for seven different drug substances from all of the classes in the Biopharmaceutics Classification System (BCS), in four different phosphate buffers. The effect of inorganic salts added as sodium chloride, sodium nitrate, sodium phosphate and sodium sulfate in the buffer media was investigated for the correlation. Triethanolammonium acetate buffer was also included in the study of the correlation of logG vs. logS. The pH was 7.0 ± 0.1 in all of the buffers to mimic a pH condition in intestinal fluids. The dissolution rate was determined with a newly constructed miniaturized rotating disk equipment, which enables fast determinations and consumes only minute quantities of substance (about 5 mg). The solubility was determined by conventional shake-flask methodology, using 1.5 mL solution volumes. All quantifications were performed with reversed phase high-performance liquid chromatography (RP-HPLC) and diode array detection (DAD). The different inorganic anions seemed to affect the solubility more than the dissolution rate. The phosphate and nitrate ions decreased the solubility for amines compared to the chloride ion. The best correlations of logG and logS were however obtained with a triethanolammonium acetate buffer. The good correlation (R2 = 0.991) may be sufficient in initial screening of drug solubility, based on dissolution rates in aqueous buffer media.

    Place, publisher, year, edition, pages
    IACMHR and SDU-DDSC, 2009
    Keywords
    dissolution rate, solubility, in vitro models, correlation, HPLC (high-performance liquid chromatography)
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-107746 (URN)
    Available from: 2010-01-11 Created: 2009-08-25 Last updated: 2018-01-13Bibliographically approved
    4. Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media
    Open this publication in new window or tab >>Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media
    2010 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 7, p. 1309-1317Article in journal (Refereed) Published
    Abstract [en]

    Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

    Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

    Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

    Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

    Keywords
    dissolution media, dissolution rate, solubility, chemometrics, miniaturized rotating disk equipment
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-112089 (URN)10.1007/s11095-010-0111-0 (DOI)000278694400012 ()20358263 (PubMedID)
    Available from: 2010-01-08 Created: 2010-01-08 Last updated: 2018-01-12Bibliographically approved
  • 234.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Baumann, Kajsa
    Inst för kemi, Göteborgs universitet.
    Sundelöf, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindberg, Walter
    AstraZeneca, Mölndal.
    Sokolowski, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3344-3355Article in journal (Refereed)
    Abstract [en]

    A miniaturized apparatus for the determination of the apparent in vitro dissolution rate has been designed, constructed and characterized. The miniaturized apparatus was based on a low volume dissolution cell and a disk in a rotating magnetic bar. The disk tablet is pressed directly into the bar with a press designed and constructed for this purpose. It requires approximately 5 mg of substance. The disk was positioned eccentrically on the bar with an external flow of medium to increase the rate of solvent flow over the disk surface. Six different drug substances were used. The dissolution media were sodium phosphate buffer, pH 7.0, and ammonium acetate buffer, pH 6.8. All quantifications were made by integrating the dissolution cell with high-performance liquid chromatography (HPLC) using diode-array detection (DAD). The obtained results were compared with data from a conventional rotating disk equipment, where the disk was centrically mounted. The dissolution rates at 100 rpm seemed to be on an average of 2-3 times higher for the miniaturized apparatus (RSD 0.2-56%). The preliminary studies of this prototype indicate that the miniaturized rotating disk is a promising design for the qualitative estimation of dissolution rates of substances, for example during screening in early drug discovery.

  • 235.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Sokolowski, Anders
    AS Consulting, Uppsala.
    Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media2009In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 114-122Article in journal (Refereed)
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and apparent solubility, S, was made for seven different drug substances from all of the classes in the Biopharmaceutics Classification System (BCS), in four different phosphate buffers. The effect of inorganic salts added as sodium chloride, sodium nitrate, sodium phosphate and sodium sulfate in the buffer media was investigated for the correlation. Triethanolammonium acetate buffer was also included in the study of the correlation of logG vs. logS. The pH was 7.0 ± 0.1 in all of the buffers to mimic a pH condition in intestinal fluids. The dissolution rate was determined with a newly constructed miniaturized rotating disk equipment, which enables fast determinations and consumes only minute quantities of substance (about 5 mg). The solubility was determined by conventional shake-flask methodology, using 1.5 mL solution volumes. All quantifications were performed with reversed phase high-performance liquid chromatography (RP-HPLC) and diode array detection (DAD). The different inorganic anions seemed to affect the solubility more than the dissolution rate. The phosphate and nitrate ions decreased the solubility for amines compared to the chloride ion. The best correlations of logG and logS were however obtained with a triethanolammonium acetate buffer. The good correlation (R2 = 0.991) may be sufficient in initial screening of drug solubility, based on dissolution rates in aqueous buffer media.

  • 236.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Sokolowski, Anders
    AS Consulting, Uppsala.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus2009In: Drug Discoveries & Therapeutics, ISSN 1881-7831, Vol. 3, no 3, p. 104-113Article in journal (Refereed)
    Abstract [en]

    A correlation of the logarithmic values of the in vitro dissolution rate, G, and the apparent solubility, S, was evaluated in phosphate and ammonium acetate buffer at an initial pH of 7. The dissolution rates were determined with a newly designed and build miniaturized rotating disk equipment, as well as with a traditional rotating disk apparatus. The two apparatuses gave the same correlation pattern of logG and logS. Thirteen diverse drug substances from all of the classes in the Biopharmaceutics Classification System (BCS) were used for the correlation in the phosphate buffer system, with the results from the miniaturized apparatus only. A coefficient of determination, R2, of 0.982 was found if bases formulated as hydrochloride salts were excluded in the correlation. The miniaturized equipment is used for rapid screening of the dissolution rate, approximately 10 min for one run, and consumes small amounts of substance (about 5 mg) and dissolution media. All quantifications were performed by using reversed phase high-performance liquid chromatography (RPHPLC) with a diode array detector (DAD), integrated with the miniaturized rotating disk equipment.

  • 237.
    Persson, Anita Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media2010In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 7, p. 1309-1317Article in journal (Refereed)
    Abstract [en]

    Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

    Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

    Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

    Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

  • 238.
    Persson, Bengt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Drug-polymer interaction in relation to surface tension and polymer properties1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Polymers are important in a variety of pharmaceutical applications. Many of them are derived from cellulose but there are several biological sources of importance for their production. Polymers display a very wide diversity of properties which makes a detailed characterization necessary. The investigated polymers are more or less surface active due to the presence of hydrophilic and hydrophobic parts. They show surface activity at very low concentrations which makes them useful as stabilizers in suspensions and emulsions. The surface tension measurements were performed by the pendant drop method.

    The surface activity and the cloud point (CP) are related to each other. These parameters depend on the hydrophilic/hydrophobic balance of the polymer. The time dependence of surface tension is mainly related to the concentration in the dynamic region (2-10 ppm). The half-life of the surface tension (t1/2) at these concentrations was found to be inversely correlated to the diffusion coefficient and to the square of the bulk concentration, which is expected for a diffusion process. Furthermore, t1/2 was related to the intrinsic viscosity of the polymers.

    The in situ colonic effective permeability of fluvastatin in the rat was found to be inversely proportional to the surface tension of fluvastatin.

    The interaction between charged amphiphiles and oppositely charged polymers was investigated by surface tension measurements since surface activity is an important property of pharmaceutical formulation. The adsorption of charged amphiphiles to oppositely charged polyelectrolytes involve charge to charge interaction at low amphiphile concentration. An increase in amphiphile concentration is followed by a cooperative increase in adsorption at a certain concentration due to hydrophobic interaction between already adsorbed amphiphiles. The strength of the interaction is related to the hydrophobicity of the amphiphile. Also the charge density isimportant since the distance between the charges influence the concentration where the hydrophobic interaction starts.

  • 239.
    Pietsch, Franziska
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Jessica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brandis, Gerrit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Marcusson, Linda L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huseby, Douglas L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ciprofloxacin selects for RNA polymerase mutations with pleiotropic antibiotic resistance effects2017In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 1, p. 75-84Article in journal (Refereed)
    Abstract [en]

    Objectives: Resistance to the fluoroquinolone drug ciprofloxacin is commonly linked to mutations that alter the drug target or increase drug efflux via the major AcrAB-TolC transporter. Very little is known about other mutations that might also reduce susceptibility to ciprofloxacin. We discovered that an Escherichia coli strain experimentally evolved for resistance to ciprofloxacin had acquired a mutation in rpoB, the gene coding for the beta-subunit of RNA polymerase. The aim of this work was to determine whether this mutation, and other mutations in rpoB, contribute to ciprofloxacin resistance and, if so, by which mechanism. Methods: Independent lineages of E. coli were evolved in the presence of ciprofloxacin and clones from endpoint cultures were screened for mutations in rpoB. Ciprofloxacin-selected rpoB mutations were identified and characterized in terms of effects on susceptibility and mode of action. Results: Mutations in rpoB were selected at a high frequency in 3 out of 10 evolved lineages, in each case arising after the occurrence of mutations affecting topoisomerases and drug efflux. All ciprofloxacin-selected rpoB mutations had a high fitness cost in the absence of drug, but conferred a competitive advantage in the presence of ciprofloxacin. RNA sequencing and quantitative RT-PCR analysis showed that expression of mdtK, encoding a multidrug efflux transporter, was significantly increased by the ciprofloxacin-selected rpoB mutations. The susceptibility phenotype was shown to depend on the presence of an active mdtK and a mutant rpoB allele. Conclusions: These data identify mutations in RNA polymerase as novel contributors to the evolution of resistance to ciprofloxacin and show that the phenotype is mediated by increased MdtK-dependent drug efflux.

  • 240.
    Poongavanam, Vasanthanathan
    et al.
    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.
    Corona, Angela
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
    Steinmann, Casper
    Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.;Aalborg Univ, Dept Chem & Biosci, Aalborg, Denmark..
    Scipione, Luigi
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Grandi, Nicole
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
    Pandolfi, Fabiana
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Di Santo, Roberto
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Costi, Roberta
    Sapienza Univ Roma, Dipartimento Chim & Tecnol Farmaco, Ist Pasteur Fdn Cenci Bolognetti, Rome, Italy..
    Esposito, Francesca
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy..
    Tramontano, Enzo
    Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy.;CNR, Ist Ric Genet & Biomed, Monserrato, CA, Italy..
    Kongsted, Jacob
    Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark..
    Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: binding mode insights through magnesium complexation and site-directed mutagenesis studies2018In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 9, no 3, p. 562-575Article in journal (Refereed)
    Abstract [en]

    Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

  • 241.
    Poongavanam, Vasanthanathan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Vigneshwaran, Namashivayam
    Univ Bonn, Pharmaceut Inst, Pharmaceut Chem 2, Bonn, Germany.
    Vanagamudi, Murugesan
    Sree Vidyanikethan Coll Pharm, Dept Med & Pharmaceut Chem, Tirupati, Andhra Prades, India.
    Hadi Al, Shamaileh
    Murdoch Univ, Ctr Comparat Genom, Perth, WA, Australia.
    Rakesh, Veedu
    Murdoch Univ, Ctr Comparat Genom, Perth, WA, Australia.; Perron Inst Neurol & Translat Sci, Perth, WA, Australia..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Murugan, N. Arul
    KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, Stockholm, Sweden.
    Integrative approaches in HIV-1 non-nucleoside reverse transcriptase inhibitor design2018In: WIREs Comput Mol Sci, Vol. 8, no 1, article id e1328Article in journal (Refereed)
  • 242.
    Potpara, Tatjana S.
    et al.
    Clin Ctr Serbia, Cardiol Clin, Belgrade, Serbia.;Univ Belgrade, Sch Med, Belgrade 11001, Serbia..
    Jokic, Vera
    Univ Belgrade, Sch Med, Belgrade 11001, Serbia..
    Dagres, Nikolaos
    Heart Ctr Leipzig, Dept Electrophysiol, Leipzig, Germany..
    Marin, Francisco
    Hosp Univ Virgen de la Arrixaca, IMIB Arrixaca, Dept Cardiol, Murcia, Spain..
    Prostran, Milica S.
    Univ Belgrade, Sch Med, Belgrade 11001, Serbia.;Univ Belgrade, Sch Med, Dept Pharmacol Clin Pharmacol & Toxicol, Belgrade, Serbia..
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lip, Gregory Y. H.
    Univ Belgrade, Sch Med, Belgrade 11001, Serbia.;Univ Birmingham, Inst Cardiovasc Sci, City Hosp, Birmingham B18 7QH, W Midlands, England..
    Cardiac Arrhythmias in Patients with Chronic Kidney Disease: Implications of Renal Failure for Antiarrhythmic Drug Therapy2016In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 23, no 19, p. 2070-2083Article, review/survey (Refereed)
    Abstract [en]

    The kidney has numerous complex interactions with the heart, including shared risk factors (e.g., hypertension, dyslipidemia, etc.) and mutual amplification of morbidity and mortality. Both cardiovascular diseases and chronic kidney disease (CKD) may cause various alterations in cardiovascular system, metabolic homeostasis and autonomic nervous system that may facilitate the occurrence of cardiac arrhythmias. Also, pre-existent or incident cardiac arrhythmias such as atrial fibrillation (AF) may accelerate the progression of CKD. Patients with CKD may experience various cardiac rhythm disturbances including sudden cardiac death. Contemporary management of cardiac arrhythmias includes the use of antiarrhythmic drugs (AADs), catheter ablation and cardiac implantable electronic devices (CIEDs). Importantly, AADs are not used only as the principal treatment strategy, but also as an adjunct therapy in combination with CIEDs, to facilitate their effects or to minimize inappropriate device activation in selected patients. Along with their principal antiarrhythmic effect, AADs may also induce cardiac arrhythmias and the risk for such proarrhythmic effect(s) is particularly increased in patients with reduced left ventricular systolic function or in the setting of electrolyte imbalance. Moreover, CKD itself can induce profound alterations in the pharmacokinetics and pharmacodynamics of many drugs including AADs, thus facilitating the drug accumulation and increased exposure. Hence, the use of AADs in patients with CKD may be challenging. In this review article, we provide an overview of the characteristics of arrhythmogenesis in patients with CKD with special emphasis on the complexity of pharmacokinetics and risk for proarrhythmias when using AADs in patients with cardiac arrhythmias and CKD.

  • 243.
    Qundos, Ulrika
    et al.
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Drobin, Kimi
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Mattsson, Cecilia
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Hong, Mun-Gwan
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Sjöberg, Ronald
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Forsström, Björn
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Solomon, David
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Uhlén, Mathias
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Nilsson, Peter
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Affin Prote, SciLifeLab, Solna, Sweden.
    Affinity proteomics discovers decreased levels of AMFR in plasma from Osteoporosis patients2016In: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 10, no 6, p. 681-690Article in journal (Refereed)
    Abstract [en]

    PURPOSE:: Affinity proteomic approaches by antibody bead arrays enable multiplexed analysis of proteins in body fluids. In the presented study, we investigated blood plasma within osteoporosis to discovery differential protein profiles and to propose novel biomarkers candidates for subsequent studies.

    EXPERIMENTAL DESIGN:: Starting with 4608 antibodies and plasma samples from 22 women for an untargeted screening, a set of 72 proteins were suggested for further analysis. Complementing these with targets from literature and other studies, a targeted bead array of was built to profile for 92 proteins in plasma samples of 180 women from two independent population-based studies.

    RESULTS:: Differential profiles between osteoporosis patients and matched controls were discovered for 12 proteins in at least one of the two study sets. Among these targets, the levels of Autocrine Motility Factor Receptor (AMFR) were concordantly lower in plasma of female osteoporosis patients. Subsequently, verification of anti-AMFR antibody selectivity was conducted using high-density peptide and protein arrays, and Western blotting.

    CONCLUSIONS AND CLINICAL RELEVANCE:: Further validation in additional study sets will be needed to determine the clinical value of the observed decrease in AMFR plasma levels in osteoporosis patients, but AMFR may aid our understanding of disease mechanisms and could support existing tools for diagnosis and monitoring of patient mobility within osteoporosis.

  • 244. RABOISSON, P. J. B.
    et al.
    BELFRAGE, Anna Karin G. L.
    CLASSON, B. O.
    LINDQUIST,, K. C.
    NILSSON, K. M.
    ROSENQUIST, Å. A. K.
    SAMUELSSON,, B. B.
    WÄHLING,, H. J.
    PYRIMIDINE SUBSTITUTED MACROCYCLIC HCV INHIBITORS2008Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Compounds of the Formula (I) including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.

  • 245.
    Ragno, Rino
    et al.
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Magma Dynamics srl, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, MO 63110, USA.
    Pirolli, Adele
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy.
    Wickersham, Richard B
    Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, MO 63110, USA.
    Patsilinakos, Alexandros
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy; Magma Dynamics srl, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ` di Roma, P. le A. Moro 5, 00185 Rome, Italy .
    Hesse, Stéphanie
    SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070 Metz, France.
    Perspicace, Enrico
    SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070 Metz, France; Genfit, Parc Eurasante ́ , 885 Avenue Euge ` ne Avine ́ e, 59120 Loss, France.
    Kirsch, Gilbert
    SRSMC UMR CNRS7565 (former LIMBP), 1 Boulevard Arago, 57070 Metz, France.
    Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches.2015In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 29, no 8, p. 757-76Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure-activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models' predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors.

  • 246.
    Ragno, Rino
    et al.
    Sapienza University of Rome.
    Marshall, Garland R.
    Washington University School of Medicine in St. Louis.
    Ballante, Flavio
    Washington University School of Medicine in St. Louis .
    Structure-based modeling and target-selectivity prediction2014Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present invention provides, inter alia, methods, models, and systems for selecting an effector having specificity for a target molecule. The methods and systems of the present invention involve several steps, including compiling a database containing structural data for a library of molecules and a population of ligands and activity data, establishing structure-based equivalence of sequence elements in the library of molecules, determining likely spatial orientations of population ligands in library molecules, calculating interaction energies for each ligand-molecule pair, generating statistical models that are predictive of sequence elements likely to contribute to a differential effect of ligands on molecules, selecting an effector that is likely to have a desired specificity for the target molecule, experimentally determining activity data for effector-library molecule pairs, and at least once repeating the steps listed above wherein the effector is a member of the population of ligands.

  • 247. Ranganathan, Anirudh
    et al.
    Stoddart, Leigh A.
    Hill, Stephen J.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models2015In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 24, p. 9578-9590Article in journal (Refereed)
    Abstract [en]

    Fragment-based lead discovery (FBLD) holds great promise for drug discovery, but applications to G protein-coupled receptors (GPCRs) have been limited by a lack of sensitive screening techniques and scarce structural information. If virtual screening against homology models of GPCRs could be used to identify fragment ligands, FBLD could be extended to numerous important drug targets and contribute to efficient lead generation. Access to models of multiple receptors may further enable the discovery of fragments that bind specifically to the desired target. to investigate these questions, we used molecular docking, to screen >500 000 fragments against homology models. of the A(3) and A(1) adenosine receptors (ARs) with the goal to discover,A(3)AR-selective ligands. Twenty-one fragments with predicted A(3)AR-specific binding were evaluated in live-cell fluorescence-based assays; of eight verified ligands, six displayed A(3)/A(1), selectivity,, and three of these had high affinities ranging from 0.1 to 1.3 mu M. Subsequently, structure-guided fragment-to-lead optimization led to the identification of a >100-fold-selective antagonist with nanomolar affinity from commercial libraries. These results highlight that molecular docking screening can guide fragment-based discovery of selective ligands even if the Structures of both the target and antitarget receptors are unknown. The same approach can be readily extended to a large number of pharmaceutically important targets.

  • 248. Razafimahefa, Solofoniaina
    et al.
    Mutulis, Felikss
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mutule, Ilze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Liepinsh, Edvards
    Dambrova, Maija
    Cirule, Helena
    Svalbe, Baiba
    Yahorava, Sviatlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yahorau, Aleh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rasolondratovo, Benoit
    Rasoanaivo, Philippe
    Wikberg, Jarl E. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Libiguins A and B: Novel Phragmalin Limonoids Isolated from Neobeguea mahafalensis Causing Profound Enhancement of Sexual Activity2014In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, no 4, p. 306-314Article in journal (Refereed)
    Abstract [en]

    In a screening programme directed towards the discovery of drugs that could enhance sexual activity, we found that a decoction of the root bark of Neobeguea mahafalensis displayed an extraordinarily high potency and remarkably long duration in augmenting sexual activity in male rodents. Bioassay-guided fractionation led to the isolation of two pharmacoactive constituents, which turned out to be novel 1,8,9-orthoacetate phragmalin limonoids that we named libiguins A and B, each with a C-16/30 -lactone ring. Chemical structures were established by the interpretation of their 1D and 2DNMR data. In vivo pharmacological tests showed that starting with a treatment from 0.004-0.4mg/kg/day for three consecutive days, over a 3-h sampling period, these limonoids induced a long-lasting augmentation of frequency and sustainment of mounting behaviour in male rodents, with an effect lasting for up to 11 days post-treatment. Libiguin A proved to be markedly more potent than libiguin B. This report is the first of limonoids having such an effect, and the findings could lead to novel therapies for the treatment of sexual dysfunction. Moreover, the results can serve as an opening to elucidate the central physiological control of mating behaviour, which is still not well mapped out.

  • 249.
    Reddy, D Rajasekhar
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Zhou, Nancy J
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States.
    Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.2017In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 127, p. 531-553, article id S0223-5234(16)31038-8Article in journal (Refereed)
    Abstract [en]

    A comprehensive investigation was performed to identify new benzodiazepine (BZD) derivatives as potent and selective human lysine deacetylase inhibitors (hKDACis). A total of 108 BZD compounds were designed, synthesized and from that 104 compounds were biologically evaluated against human lysine deacetylases (hKDACs) 1, 3 and 8 (class I) and 6 (class IIb). The most active compounds showed mid-nanomolar potencies against hKDACs 1, 3 and 6 and micromolar activity against hKDAC8, while a promising compound (6q) showed selectivity towards hKDAC3 among the different enzyme isoforms. An hKDAC6 homology model, refined by molecular dynamics simulation was generated, and molecular docking studies performed to rationalize the dominant ligand-residue interactions as well as to define structure-activity-relationships. Experimental results confirmed the usefulness of the benzodiazepine moiety as capping group when pursuing hKDAC isoform-selectivity inhibition, suggesting its continued use when designing new hKDACis.

  • 250.
    Reddy, Damodara N
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Chuang, Timothy
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Pirolli, Adele
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Marrocco, Biagina
    Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Marshall, Garland R
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
    Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 4, p. 1613-33Article in journal (Refereed)
    Abstract [en]

    Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.

2345678 201 - 250 of 358
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