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  • 2001.
    Yu, Z
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Influence of mobile phase conditions on the clean-up effect of restricted-access media precolumns for plasma samples injected in a column-switching system1997Ingår i: CHROMATOGRAPHIA, Vol. 44, s. 589-Artikel i tidskrift (Refereegranskat)
  • 2002.
    Yu, ZX
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Direct injection of large volumes of plasma in a column-switching system for the analysis of local anaesthetics .1. Optimization of semi-permeable surface precolumns in the system and characterization1996Ingår i: JOURNAL OF CHROMATOGRAPHY A, Vol. 725, s. 137-Artikel i tidskrift (Refereegranskat)
  • 2003.
    Yu, ZX
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Direct injection of large volumes of plasma in a column-switching system for the analysis of local anaesthetics .2. Determination of bupivacaine in human plasma with an alkyl-diol silica precolumn1996Ingår i: JOURNAL OF CHROMATOGRAPHY A, Vol. 725, s. 149-Artikel i tidskrift (Refereegranskat)
  • 2004.
    Yu, ZX
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Ion-pair chromatography of methotrexate in a column-switching system using an alkyl-diol silica precolumn for direct injection of plasma1996Ingår i: JOURNAL OF CHROMATOGRAPHY A, Vol. 742, s. 113-Artikel i tidskrift (Refereegranskat)
  • 2005.
    Yu, ZX
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Boos, KS
    Determination of methotrexate and its metabolite 7-hydroxymethotrexate by direct injection of human plasma into a column-switching liquid chromatographic system using post-column photochemical reactio1997Ingår i: JOURNAL OF CHROMATOGRAPHY B, Vol. 689, s. 379-Artikel i tidskrift (Refereegranskat)
  • 2006.
    Yu, ZX
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Boos, KS
    Evaluation of liquid chromatographic behavior of restricted-access media precolumns in the course of direct injection of large volumes of plasma samples in column-switching systems1997Ingår i: JOURNAL OF CHROMATOGRAPHY B, Vol. 704, s. 53-Artikel i tidskrift (Refereegranskat)
  • 2007. Zahedifard, Maryam
    et al.
    Faraj, Fadhil Lafta
    Paydar, Mohammadjavad
    Looi, Chung Yeng
    Hasandarvish, Pouya
    Hajrezaie, Maryam
    Kamalidehghan, Behnam
    Majid, Nazia Abdul
    Khalifa, Shaden A. M.
    Ali, Hapipah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells2015Ingår i: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 21, nr 23, s. 3417-3426Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2-hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 +/- 0.71 mu g/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.

  • 2008.
    Zahra, Maram Hussein
    et al.
    Okayama Univ, Grad Sch Nat Sci & Technol, Div Chem & Biotechnol, Okayama 7008530, Japan.
    Salem, Tarek A. R.
    Qassim Univ, Dept Biochem, Coll Med, Al Qassim 51452, Saudi Arabia;Univ Sadat City, Genet Engn & Biotechnol Inst, Dept Mol Biol, Sadat City 32958, Egypt.
    El-Aarag, Bishoy
    Okayama Univ, Grad Sch Nat Sci & Technol, Div Chem & Biotechnol, Okayama 7008530, Japan;Menoufia Univ, Div Biochem, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Yosri, Nermeen
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    EL-Ghlban, Samah
    Menoufia Univ, Div Biochem, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Zaki, Kholoud
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Marei, Amel H.
    Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt.
    Abd El-Wahed, Aida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt;Agr Res Ctr, Plant Protect Res Inst, Dept Bee Res, Giza 12627, Egypt.
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Khatib, Alfi
    Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Fac Pharm, Kuantan 25200, Pahang, Malaysia.
    AlAjmi, Mohamed F.
    King Saud Univ, Coll Pharm, Pharmacognosy Grp, Riyadh 11451, Saudi Arabia.
    Shathili, Abdulrahman M.
    Al Rayan Coll, Al Rayan Res & Innovat Ctr, Medina 42541, Saudi Arabia.
    Xiao, Jianbo
    Univ Macau, Inst Chinese Med Sci, Taipa 999078, Macau, Peoples R China.
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Clin Res Ctr, S-14186 Huddinge, Sweden;Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, SE-10691 Stockholm, Sweden.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Menoufia Univ, Dept Chem, Fac Sci, Shibin Al Kawm 32512, Egypt;Al Rayan Coll, Al Rayan Res & Innovat Ctr, Medina 42541, Saudi Arabia;Jiangsu Univ, Coll Food & Biol Engn, Zhenjiang 212013, Jiangsu, Peoples R China.
    Alpinia zerumbet (Pers.): Food and Medicinal Plant with Potential In Vitro and In Vivo Anti-Cancer Activities2019Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, nr 13, artikel-id 2495Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Aim: Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers.

    Methods: The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model.

    Results: A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, H-1-NMR and C-13-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 mu g/mL, respectively.

    Conclusion: Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet.

  • 2009. Zahran, Moustafa
    et al.
    El-Kemary, Maged
    Khalifa, Shaden
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Spectral studies of silver nanoparticles biosynthesized by Origanum majorana2018Ingår i: Green Processing and Synthesis, ISSN 2191-9542, E-ISSN 2191-9550, Vol. 7, nr 2, s. 100-105Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Silver nanoparticles (AgNPs) were biologically synthesized in an eco-friendly manner using aqueous leaf extract of Origanum majorana plant and silver nitrate (AgNO 3) solution. Size, shape, and crystallinity of the biosynthesized AgNPs were determined by using a transmission electron microscope (TEM). Zeta potential analyzer was used to prove the stability of the metallic nanoparticles, while Fourier transform infrared spectroscopy was used to identify the bioreducing and capping agents. AgNPs were electrochemically investigated using cyclic voltammetry (CV), while the optical properties of the metallic nanoparticles were studied using UV-Vis and fluorescence spectroscopies. According to TEM images, AgNPs are spherical with an average size of 35 nm. TEM also refers to the presence of mono and polycrystalline AgNPs. The value of zeta potential (-39 mV) proved the stability of AgNPs caused by capping molecules of O. majorana plant. CV studies showed that AgNPs were electrochemically investigated at 0.39 mV. AgNPs showed a surface plasmon resonance peak at 440 nm, while the emission peak was detected at 466 nm. These nanoparticles are promising for many industrial and medical applications.

  • 2010. Zajmi, Asdren
    et al.
    Hashim, Najihah Mohd
    Noordin, Mohamed Ibrahim
    Khalifa, Shaden A. M.
    Ramli, Faiqah
    Ali, Hapipah Mohd
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ultrastructural Study on the Antibacterial Activity of Artonin E versus Streptomycin against Staphylococcus aureus Strains2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, artikel-id e0128157Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Staphylococci are facultative anaerobes, perfectly spherical un-encapsulated cocci, with a diameter not exceeding 1 micrometer in diameter. Staphylococcus aureus are generally harmless and remain confined to the skin unless they burrow deep into the body, causing life-threatening infections in bones, joints, bloodstream, heart valves and lungs. Among the 20 medically important staphylococci species, Staphylococcus aureus is one of the emerging human pathogens. Streptomycin had its highest potency against Staphylococcus infections despite the likelihood of getting a resistant type of staphylococcus strains. Methicillin-resistant S. aureus (MRSA) is the persister type of Staphylococcus aureus and was evolved after decades of antibiotic misuse. Inadequate penetration of the antibiotic is one of the principal factors related to success/failure of the therapy. The active drug needs to reach the bacteria at concentrations necessary to kill or suppress the pathogen's growth. In turn the effectiveness of the treatment relied on the physical properties of Staphylococcus aureus. Thus understanding the cell integrity, shape and roughness is crucial to the overall influence of the therapeutic agent on S. aureus of different origins. Hence our experiments were designed to clarify ultrastructural changes of S. aureus treated with streptomycin (synthetic compound) in comparison to artonin E (natural compound). In addition to the standard in vitro microbial techniques, we used transmission electron microscopy to study the disrupted cell architecture under antibacterial regimen and we correlate this with scanning electron microscopy (SEM) to compare results of both techniques.

  • 2011. Zamora, Ismael
    et al.
    Afzelius, Lovisa
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Cruciani, Gabriele
    Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.2003Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, nr 12, s. 2313-2324Artikel i tidskrift (Refereegranskat)
  • 2012. Zheng, Ming
    et al.
    Appel, Lieuwe
    Luo, Feng
    Lane, Roger
    Risinger, Robert
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Cahir, Matthews
    Sanjay, Keswani
    Hayes, Wendy
    Burt, David
    Zubin, Bhagwaragar
    Safety, Pharmacokinetic, and Positron Emission Tomography Evaluation of Serotonin and Dopamine Transporter Occupancy Following Multiple-Dose Administration of the Triple Monoamine Reuptake Inhibitor BMS-8208362015Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, nr 3, s. 529-540Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rationale

    BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.

    Objective

    This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [11C]MADAM or [11C]PE2I, respectively.

    Methods

    Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1–4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4–8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.

    Results

    Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0–5.5 h post-dose; estimated elimination half-life was 44–74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.

    Conclusions

    Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

  • 2013.
    Zhou, Qin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Carlsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Botros, Milad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Fransson, Rebecca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Hallberg, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The C-terminal amidated analogue of the Substance P (SP) fragment SP (1-7) attenuates the expression of naloxone- precipitated withdrawal in morphine dependent rats2009Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 30, nr 12, s. 2418-2422Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We previously demonstrated that intracerebroventricular (i.c.v.) administration of the substance P (SP) aminoterminal fragment SP(1-7) attenuates the expression of morphine withdrawal in the male rat. In this study we have used a synthetic analogue of this peptide, i.e. the SP(1-7) amide showing higher binding potency than the native heptapeptide, in a similar experimental set-up. Thus, Wistar male rats were made tolerant to morphine by daily injections of the opiate during 8 days. Following peptide administration (i.c.v.) and a subsequent naloxone challenge a variety of physical syndromes of withdrawal were recorded. We observed that the SP(1-7) amide potently and dose-dependently reduced several signs of reaction to morphine withdrawal. Interestingly, the effect of the peptide amide was significantly attenuated by the addition of the sigma agonist (+)-SKF-10047. We conclude that the SP(1-7) amide mimics the effect of the native SP fragment and that the mechanisms for its action involve a sigma receptor site.

  • 2014. Zuccarello, Guido
    et al.
    Bouzide, Abderrahim
    Kvarnstrom, Ingemar
    Niklasson, Gunilla
    Svensson, Stefan C. T.
    Brisander, Magnus
    Danielson, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Nillroth, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karlen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Classon, Björn
    Samuelsson, Bertil
    HIV-1 protease inhibitors based on acyclic carbohydrates1998Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 63, nr 15, s. 4898-4906Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.

  • 2015.
    Zumberge, J. Alex
    et al.
    Univ Calif Riverside, Dept Earth Sci, Riverside, CA 92521 USA.
    Love, Gordon D.
    Univ Calif Riverside, Dept Earth Sci, Riverside, CA 92521 USA.
    Cárdenas, Paco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Sperling, Erik A.
    Stanford Univ, Dept Geol Sci, Stanford, CA 94305 USA.
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Rohrssen, Megan
    Cent Michigan Univ, Dept Earth & Atmospher Sci, Mt Pleast, MI USA.
    Grosjean, Emmanuelle
    Geosci Australia, Canberra, ACT, Australia.
    Grotzinger, John P.
    CALTECH, Div Geol & Planetary Sci, Pasadena, CA USA.
    Summons, Roger E.
    MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA USA.
    Demosponge steroid biomarker 26-methylstigmastane provides evidence for Neoproterozoic animals2018Ingår i: Nature Ecology & Evolution, E-ISSN 2397-334X, Vol. 2, nr 11, s. 1709-1714Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sterane biomarkers preserved in ancient sedimentary rocks hold promise for tracking the diversification and ecological expansion of eukaryotes. The earliest proposed animal biomarkers from demosponges (Demospongiae) are recorded in a sequence around 100 Myr long of Neoproterozoic-Cambrian marine sedimentary strata from the Huqf Supergroup, South Oman Salt Basin. This C-30 sterane biomarker, informally known as 24-isopropylcholestane (24-ipc), possesses the same carbon skeleton as sterols found in some modern-day demosponges. However, this evidence is controversial because 24-ipc is not exclusive to demosponges since 24-ipc sterols are found in trace amounts in some pelagophyte algae. Here, we report a new fossil sterane biomarker that co-occurs with 24-ipc in a suite of late Neoproterozoic-Cambrian sedimentary rocks and oils, which possesses a rare hydrocarbon skeleton that is uniquely found within extant demosponge taxa. This sterane is informally designated as 26-methylstigmastane (26-mes), reflecting the very unusual methylation at the terminus of the steroid side chain. It is the first animal-specific sterane marker detected in the geological record that can be unambiguously linked to precursor sterols only reported from extant demosponges. These new findings strongly suggest that demosponges, and hence multicellular animals, were prominent in some late Neoproterozoic marine environments at least extending back to the Cryogenian period.

  • 2016.
    Åberg, Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Combinatorial synthesis of labelled drugs and PET tracers: synthesis of a focused library of 11C-carbonyl-labelled acrylamides as potential biomarkers of EGFR expression2012Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 55, nr 14, s. 477-483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 2017.
    Åberg, Ola
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Stevens, Marc
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindh, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. ORGFARM.
    Wallinder, Charlotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hall, Håkan
    Monazzam, Azita
    Uppsala Imanet, GE Healthcare.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Synthesis and evaluation of a 11C-labelled angiotensin II AT2 receptor ligand2010Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 53, nr 10, s. 616-624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Three C-11-radiolabelled high-affinity nonpeptide AT(2) receptor-selective ligands were synthesized and one of these was evaluated as positron emission tomography (PET) tracer. The labelling reaction was performed via palladium(0)-mediated aminocarbonylation of the aryl iodide substrate using [C-11] carbon monoxide as the labelled precursor. As an example, starting with 10.0 GBq [C-11] carbon monoxide, 1.10 GBq of the product N-butoxycarbonyl-3-[4-(N-benzyl-[C-11] carbamoyl)phenyl]-5-isobutylthiophene-2-sulphonamide [C-11]4d was obtained in 36% decay-corrected radiochemical yield (from [C-11] carbon monoxide), 42 min from end of bombardment with a specific activity of 110 GBq.mu mol(-1). The N-isopropyl-[C-11] carbamoyl-analogue [C-11]4c (radiochemical purity >95%) was studied employing autoradiography, organ distribution, and small animal PET. In vitro autoradiography showed specific binding in the pancreas and kidney. Organ distribution in six rats revealed a high uptake in the liver, intestine, kidney, and adrenals. Small animal PET showed rapid and reversible uptake in the kidneys followed by accumulation in the urinary bladder suggesting fast renal excretion of the tracer. In addition, high accumulation was also seen in the liver. For future studies, more metabolically stable tracers will need to be developed. To the best of our knowledge, this is the first attempt of the use of PET imaging for the detection of expressed, fully functional AT(2) receptors in living subjects.

  • 2018.
    Åberg, Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Varasteh, Zohreh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    (AlF)-F-18-labelling of NOTA-P2-RM26 and its evaluation as a PET ligand for GRPR/BB22013Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, nr S1, s. S404-S404Artikel i tidskrift (Övrigt vetenskapligt)
  • 2019.
    Åkerbladh, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium(0)-Catalysed Carbonylative Multicomponent Reactions: Synthesis of Heterocycles and the Application of Quinolinyl Pyrimidines as Enzyme Inhibitors2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

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

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

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

    Delarbeten
    1. Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
    Öppna denna publikation i ny flik eller fönster >>Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source
    Visa övriga...
    2015 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, nr 3, s. 1464-1471Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-249019 (URN)10.1021/jo502400h (DOI)000349934600019 ()25575042 (PubMedID)
    Tillgänglig från: 2015-04-24 Skapad: 2015-04-10 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
    2. Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide
    Öppna denna publikation i ny flik eller fönster >>Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide
    2016 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, nr 7, s. 2966-2973Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-295556 (URN)10.1021/acs.joc.6b00249 (DOI)000373520200028 ()26967689 (PubMedID)
    Tillgänglig från: 2016-06-22 Skapad: 2016-06-08 Senast uppdaterad: 2017-11-28Bibliografiskt granskad
    3. Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide
    Öppna denna publikation i ny flik eller fönster >>Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide
    2017 (Engelska)Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 6, nr 5, s. 620-628Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-329967 (URN)10.1002/open.201700130 (DOI)000413038400003 ()29046856 (PubMedID)
    Tillgänglig från: 2017-09-24 Skapad: 2017-09-24 Senast uppdaterad: 2018-02-05Bibliografiskt granskad
    4. Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylguanidines
    Öppna denna publikation i ny flik eller fönster >>Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylguanidines
    (Engelska)Ingår i: Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-329968 (URN)
    Tillgänglig från: 2017-09-24 Skapad: 2017-09-24 Senast uppdaterad: 2017-09-24
    5. Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
    Öppna denna publikation i ny flik eller fönster >>Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
    Visa övriga...
    (Engelska)Ingår i: Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-329969 (URN)
    Tillgänglig från: 2017-09-24 Skapad: 2017-09-24 Senast uppdaterad: 2018-01-13
  • 2020.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Chow, Shiao Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide2017Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 6, nr 5, s. 620-628Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 2021.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lu, Lu
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Konda, Konda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Cao, Sha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Vocat, Anthony
    Maes, Louis
    Cole, Stewart T.
    Hughes, Diarmaid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Mowbray, Sherry
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)Ingår i: Artikel i tidskrift (Övrigt vetenskapligt)
  • 2022.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wejdemar, Matyas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source2015Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, nr 3, s. 1464-1471Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 2023.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-lodoanilines and Cyanamide2016Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, nr 7, s. 2966-2973Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 2024.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Palladium-Catalyzed Molybdenum Hexacarbonyl-Mediated Gas-Free Carbonylative Reactions2019Ingår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 30, nr 2, s. 141-155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This account summarizes Pd(0)-catalyzed Mo(CO) 6-mediated gas-free carbonylative reactions published in the period October 2011 to May 2018. Presented reactions include inter-and intramolecular carbonylations, carbonylative cross-couplings, and carbonylative multicomponent reactions using Mo(CO) 6 as a solid source of CO. The presented methodologies were developed mainly for 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 vials or by using two-chamber solutions. 1 Introduction 2 Recent Developments 2.1 New CO Sources 2.2 Two-Chamber System for ex Situ CO Generation 2.3 Multicomponent Carbonylations 3 Carbonylations with N and O Nucleophiles 4 Carbonylative Cross-Coupling Reactions with Organometallics 5 Carbonylative Cascade Reactions 6 Carbonylative Cascade, Multistep Reactions 7 Summary and Outlook

  • 2025.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Schembri, Luke S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Odell, Luke R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N-Acylguanidines2017Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, nr 23, s. 12520-12529Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A convenient synthetic strategy toward N-acylguanidines via a sequential one-pot multicomponent carbonylation/amination reaction has been developed. The compounds were readily obtained via an N-cyanobenzamide intermediate formed from the Pd(0)-catalyzed carbonylative coupling of cyanamide and aryl iodides or bromides. Subsequent amination with a large variety of amines provided the final N-acylguanidines, with the overall formation of one C-C and two C-N bonds, in moderate to excellent yields. The substrate scope was found to be wide and the methodology was used to produce over 50 compounds, including 29 novel molecules. Furthermore, three separate nitrogen-containing heterocycles were prepared from the N-acylguanidines synthesized using the developed multicomponent, carbonylative method.

  • 2026.
    Åkerbladh, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Schembri, Luke S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Odell, Luke R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Palladium(0)-Catalyzed Carbonylative Synthesis of N-AcylguanidinesIngår i: Artikel i tidskrift (Övrigt vetenskapligt)
  • 2027.
    Öhrngren, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Tertiary Alcohol- or β-Hydroxy γ-Lactam-Based HIV-1 Protease Inhibitors: Microwave Applications in Batch and Continuous Flow Organic Synthesis2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Since the outbreak of the HIV/AIDS pandemic in the 1980s, the disease has cost the lives of over 30 million people, and a further 33 million are currently living with the HIV infection. With the appropriate treatment, HIV/AIDS can today be regarded as a chronic but manageable disease. However, treatment is not available globally and UNAIDS still estimates that there are currently 5000 AIDS-related deaths worldwide per day.

    HIV protease inhibitors (PIs) constitute one of the fundaments of HIV treatment, and are commonly used in so-called highly active antiretroviral therapy (HAART), together with reverse transcriptase inhibitors. Although there are ten PIs on the market, there is still a need for novel structures. The rapid development of resistant strains, due to the high frequency of mutations, together with the commonly observed adverse effects of the drugs available, illustrate the need to develop new potent structures.

    Two novel scaffolds were investigated in this work. A tertiary alcohol-containing scaffold comprising a three-carbon tether, and a β-hydroxy γ-lactam-based scaffold were designed, synthesized and evaluated using enzyme- and cell-based assays. X-ray analyses of inhibitors from each class provided information on inhibitor–protease interactions. The inhibitors containing the tertiary alcohol provided at best an enzymatic inhibition (Ki) of 2.3 nM, and an inhibition in the cell-based assay (EC50) of 0.17 µM. The γ-lactam-based inhibitors exhibited better inhibition than the first series; the best values being Ki = 0.7 nM and EC50 = 0.04 µM.

    The second part of these studies involved the evaluation of a novel non-resonance continuous-flow microwave instrument. The instrument was validated regarding heating capacity, temperature stability and temperature homogeneity. A number of model reactions were performed with low- and high-microwave-absorbing solvents. It was found that the microwave heating source allowed rapid temperature adjustment, together with easily regulated, flow-dependent reaction times, providing an efficient tool for reaction optimisation.

    Delarbeten
    1. Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
    Öppna denna publikation i ny flik eller fönster >>Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
    Visa övriga...
    2008 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, nr 4, s. 1053-1057Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-102908 (URN)10.1021/jm070680h (DOI)000253353800037 ()18215014 (PubMedID)
    Tillgänglig från: 2009-05-12 Skapad: 2009-05-12 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
    Öppna denna publikation i ny flik eller fönster >>Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
    Visa övriga...
    2011 (Engelska)Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, nr 8, s. 701-709Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.

    Nyckelord
    HIV, protease, inhibitor
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-135157 (URN)10.1039/c1md00077b (DOI)000295068100003 ()
    Tillgänglig från: 2010-12-06 Skapad: 2010-12-06 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Öppna denna publikation i ny flik eller fönster >>Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
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    2012 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 6, s. 2724-2736Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

    Nyckelord
    HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-160186 (URN)10.1021/jm201620t (DOI)000301767000017 ()
    Tillgänglig från: 2011-10-17 Skapad: 2011-10-17 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    4. Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
    Öppna denna publikation i ny flik eller fönster >>Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications
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    2012 (Engelska)Ingår i: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, nr 5, s. 1053-1063Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20 degrees C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm X (sic) 3 mm tubular borosilicate reactor and a flow between 47 and 2120 mu L/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels-Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.

    Nyckelord
    non-resonant, microwave, Continuous-Flow, MAOS, CF-MAOS
    Nationell ämneskategori
    Läkemedelskemi Organisk kemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-160187 (URN)10.1021/op300003b (DOI)000304129100036 ()
    Tillgänglig från: 2011-10-17 Skapad: 2011-10-17 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
  • 2028.
    Öhrngren, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fardost, Ashkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Russo, Francesco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Fagrell, Magnus
    WaveCraft AB.
    Schanche, Jon-Sverre
    WaveCraft AB.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications2012Ingår i: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 16, nr 5, s. 1053-1063Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20 degrees C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm X (sic) 3 mm tubular borosilicate reactor and a flow between 47 and 2120 mu L/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels-Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.

  • 2029.
    Öhrngren, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wu, Xiongyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Persson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Ekegren, Jenny
    Wallberg, Hans
    Vrang, Lotta
    Rosenquist, Åsa
    Samuelsson, Bertil
    Unge, Torsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents2011Ingår i: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, nr 8, s. 701-709Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.

  • 2030.
    Örlefors, Håkan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Garske, Ulrike
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Juhlin, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Öberg, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Onkologisk endokrinologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Endokrin tumörbiologi.
    Långstrom, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Bergström, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Whole-Body 11C-5-Hydroxytryptophan Positron Emission Tomography as a Universal Imaging Technique for Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and Computed Tomography2005Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 90, nr 6, s. 3392-3400Artikel i tidskrift (Refereegranskat)
  • 2031.
    Örtqvist, Pernilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    On the Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: From Tripeptides to Achiral Compounds2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Infection by the hepatitis C virus (HCV) leads to inflammation of the liver, i.e. hepatitis. The acute infection often progresses to a chronic phase during which the liver function is gradually impaired. Approximately 20% of these chronic cases develop liver cirrhosis, with an ensuing increased risk of liver cancer. Global estimates of the total number of chronic cases range from 123–170 million. Yet, neither specific anti-HCV drugs nor vaccines are available. When drugs become available for daily clinical use, rapid development of drug-resistant strains is expected, making resistance an important issue.

    One of the most studied targets for specific anti-HCV drugs is the NS3 protease. The main objectives of the work presented in this thesis were to design and synthesise peptidomimetic inhibitors of this enzyme, and to establish the structure–activity relationships (SARs) regarding the inhibition of the wild type as well as of the known resistant variants A156T and D168V.

    Substituted prolines are common P2 residues in HCV NS3 protease inhibitors. To decrease the peptide character of the inhibitors, the non-coded phenylglycine was evaluated as a proline replacement in combination with known and novel P3 and P1 residues and P2 substituents. The results confirmed that phenylglycine is a promising P2 scaffold, with a possible π-stacking interaction with histidine 57 of the active site. However, to benefit from its full potential, additional optimisation is required.

    A 2(1H)-pyrazinone-based scaffold was introduced as P3 residue. Utilising the scope of the method developed for the pyrazinone scaffold synthesis, the phenylglycine side-chain was transferred to the scaffold. In combination with an aromatic P1 building-block, this design yielded achiral, peptidomimetic inhibitors, three times more potent than the tripeptide lead.

    The SARs for the inhibition of the resistant variants A156T and D168V were investigated for compounds based on either P2 proline or phenyl­glycine. It was concluded that the vulnerability of the inhibitors to alterations in the enzyme depends on the P2 and the P1 residue, not only on the P2 as previously suggested.

    These results provide important information for the design of a new generation of inhibitors with improved properties.

    Delarbeten
    1.
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    2. Structure-Activity Relationships of HCV NS3 Protease Inhibitors Evaluated on the Drug-Resistant Variants A156T and D168V
    Öppna denna publikation i ny flik eller fönster >>Structure-Activity Relationships of HCV NS3 Protease Inhibitors Evaluated on the Drug-Resistant Variants A156T and D168V
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-111363 (URN)
    Tillgänglig från: 2009-12-16 Skapad: 2009-12-11 Senast uppdaterad: 2018-01-12