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  • 1. Abdel-Hamid, Mohammed K
    et al.
    Macgregor, Kylie A
    Odell, Luke R
    Chau, Ngoc
    Mariana, Anna
    Whiting, Ainslie
    Robinson, Phillip J
    McCluskey, Adam
    1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity.2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 29Article in journal (Refereed)
    Abstract [en]

    Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.

  • 2.
    Axelsson, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Veron, Jean-Baptiste
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    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.
    An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles2014In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, no 15, p. 2376-2380Article in journal (Refereed)
    Abstract [en]

    A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

  • 3.
    Bergman, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nordeman, Patrik
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 10, article id 1688Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography is an imaging technique with applications in clinical settings as well as in basic research for the study of biological processes. A PET tracer, a biologically active molecule where a positron-emitting radioisotope such as carbon-11 has been incorporated, is used for the studies. Development of robust methods for incorporation of the radioisotope is therefore of the utmost importance. The urea functional group is present in many biologically active compounds and is thus an attractive target for incorporation of carbon-11 in the form of [C-11] carbon monoxide. Starting with amines and [C-11] carbon monoxide, both symmetrical and unsymmetrical C-11-labelled ureas were synthesised via a palladium(II)-mediated oxidative carbonylation and obtained in decay-corrected radiochemical yields up to 65%. The added advantage of using [C-11] carbon monoxide was shown by the molar activity obtained for an inhibitor of soluble epoxide hydrolase (247 GBq/mu mol-319 GBq/mu mol). DFT calculations were found to support a reaction mechanism proceeding through an C-11-labelled isocyanate intermediate.

  • 4.
    Chow, Shiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Stevens, Marc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides2016In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 7, p. 2681-2691Article in journal (Refereed)
    Abstract [en]

    An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)(6), were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed.

  • 5.
    Chow, Shiao Y.
    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.
    Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas from Sulfonyl Azides, Carbon Monoxide, and Amides2017In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 5, p. 2515-2522Article in journal (Refereed)
    Abstract [en]

    A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from sulfonyl azides, followed by a [2 + 2] cycloaddition with amides and subsequent decarboxylation, which liberates the desired sulfonyl amidines, generating N-2 and CO2 as the only reaction byproducts. Using this simple protocol, a diverse range of sulfonyl amidines was obtained in moderate to excellent yields. In addition, the reaction can also be directed through a more conventional amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl sulfonyl ureas in good yields.

  • 6.
    Chow, Shiao Y.
    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.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Low-Pressure Radical C-11-Aminocarbonylation of Alkyl Iodides through Thermal Initiation2016In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 36, p. 5980-5989Article in journal (Refereed)
    Abstract [en]

    A radical C-11-aminocarbonylation protocol characterized by excellent substrate compatibility was developed to transform alkyl iodides into C-11-labelled amides, including the 11-HSD1 inhibitor [carbonyl-C-11]adamantan-1-yl(piperidin-1-yl)methanone. This protocol serves as a complementary extension of palladium-mediated C-11-aminocarbonylation, which is limited to the preparation of C-11-labelled compounds lacking beta-hydrogen atoms. The use of AIBN as a radical initiator and a low-pressure xenon-[C-11]CO delivery unit represents a simple and convenient alternative to previous radical C-11-carbonylation methodologies burdened with the need for a proprietary high pressure reactor connected to a light source.

  • 7.
    Chow, Shiao Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Stevens, Marc Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerbladh, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Sara
    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.
    Mild and Low-Pressure fac-Ir(ppy)3-Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible-Light Photoredox Catalysis2016In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 27, p. 9155-9161Article in journal (Refereed)
    Abstract [en]

    A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)(3)-catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)(3), amines, reductants, and CO gas (released ex situ from Mo(CO)(6)), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.

  • 8.
    De Rosa, Maria
    et al.
    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.
    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.
    Syntheses of new tuberculosis inhibitors promoted by microwave irradiation2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 181-191Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis (TB) represents a major public health problem. The growing number of (extensively) multi-drug resistance cases indicates that there is an urgent need for discovery of new anti-TB entities, addressed towards new and specific targets, and continuous development of fast and efficient synthetic strategies to access them easily. Microwave-assisted chemistry is well suited for small-scale laboratory synthetic work, allowing full control of reaction conditions, such as temperature, pressure, and time. Microwave-assisted high-speed organic synthesis is especially useful in the lead optimization phase of drug discovery. To illustrate the advantages of modern microwave heating technology, we herein describe applications and approaches that have been useful for the synthesis of new drug-like anti-TB compounds.

  • 9.
    Desroses, Matthieu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wieckowski, Krzysztof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Stevens, Marc
    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.
    A microwave-assisted, propylphosphonic anhydride (T3P (R)) mediated one-pot Fischer indole synthesis2011In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 52, no 34, p. 4417-4420Article in journal (Refereed)
    Abstract [en]

    A rapid, mild, and high yielding protocol for the Fischer indolization of arylhydrazines with T3P (R) under microwave irradiation is described. Significant features of this method include short reaction times and preparative ease.

  • 10. Garner, J.
    et al.
    Hill, T.
    Odell, L.R.
    Keller, P.
    Morgan, J.
    McCluskey, A.
    Identification of Aminopyrimidine Regioisomers via Line Broadening Effects in 1H and 13C NMR Spectroscopy2004In: Australian Journal of Chemistry, Vol. 57, no 11, p. 1079-1083Article in journal (Refereed)
    Abstract [en]

    Substituted mono- and diamino-pyrimidines were synthesized as part of our medicinal chemistry programmes. Primary amines substituted at the 4-position exhibited room-temperature line broadening effects in both 1H and 13C NMR spectroscopy due to the presence of rotamers, but these effects were not observed for substituents in the 2-position. This provided a simple diagnostic tool for the identification of regioisomers, a determination which would otherwise have required two-dimensional experiments.

  • 11.
    Gising, Johan
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Odell, Luke R
    University of Newcastle, Australia.
    Microwave-assisted synthesis of anti-tuberculosis, HIV and hepatitis C agents2014In: Microwaves in Drug Discovery and Development: Recent Advances, Future Medicine , 2014, p. 34-54Chapter in book (Refereed)
    Abstract [en]

    Microwave heating technology is ideally suited to small-scale discovery chemistry applications, as it allows for full reaction control, rapid (super)heating, short reaction times, high safety and rapid feedback. These unique properties offer unparalleled opportunities for medicinal chemists to speed up the lead optimization process in early drug discovery. To illustrate these advantages, we herein describe a number of recent applications of dedicated microwave instrumentation in the synthesis of small molecules targeting three of the most prevalent infectious diseases: tuberculosis, HIV/AIDS and hepatitis C.

  • 12.
    Gising, Johan
    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.
    Odell, Luke R
    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.
    Lindh, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Iyer, Harini
    AstraZeneca India.
    Sinha, Achyut M
    AstraZeneca India.
    Srinivasa, Bachally R
    AstraZeneca 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.
    Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, p. 2894-2898Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis glutamine synthetase (MtGS) is a promising target for antituberculosis drug discovery. In a recent high-throughput screening study we identified several classes of MtGS inhibitors targeting the ATP-binding site. We now explore one of these classes, the 2-tert-butyl-4,5-diarylimidazoles, and present the design, synthesis, and X-ray crystallographic studies leading to the identification of MtGS inhibitors with submicromolar IC(50) values and promising antituberculosis MIC values.

  • 13.
    Gising, Johan
    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.
    Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C2012In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 10, no 14, p. 2713-2729Article in journal (Refereed)
    Abstract [en]

    The unique properties of microwave in situ heating offer unparalleled opportunities for medicinal chemists to speed up lead optimisation processes in early drug discovery. The technology is ideal for small-scale discovery chemistry because it allows full reaction control, short reaction times, high safety and rapid feedback. To illustrate these advantages, we herein describe applications and approaches in the synthesis of small molecules to combat four of the most prevalent infectious diseases; tuberculosis, HIV/AIDS, malaria and hepatitis C, using dedicated microwave instrumentation.

  • 14. Hill, Timothy A
    et al.
    Gordon, Christopher P
    McGeachie, Andrew B
    Venn-Brown, Barbara
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Chau, Ngoc
    Quan, Annie
    Mariana, Anna
    Sakoff, Jennette A
    Chircop, Megan
    Robinson, Phillip J
    McCluskey, Adam
    Inhibition of dynamin mediated endocytosis by the dynoles: synthesis and functional activity of a family of indoles2009In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, no 12, p. 3762-3773Article in journal (Refereed)
    Abstract [en]

    Screening identified two bisindolylmaleimides as 100 microM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 +/- 0.3 microM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC(50) approximately 15 microM; RME IC(50) approximately 80 microM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.

  • 15. Hill, Timothy A.
    et al.
    Mariana, Anna
    Gordon, Christopher P.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Robertson, Mark J.
    McGeachie, Andrew B.
    Chau, Ngoc
    Daniel, James A.
    Gorgani, Nick N.
    Robinson, Phillip J.
    McCluskey, Adam
    Iminochromene Inhibitors of Dynamins I and II GTPase Activity and Endocytosis2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 10, p. 4094-4102Article in journal (Refereed)
    Abstract [en]

    Herein we report the synthesis of discrete iminochromene (“iminodyn”) libraries (1438) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC50 values of 260 nM to 100 μM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC50 values of 330 ± 70, 450 ± 50, and 260 ± 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP. Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I), with 17 showing no activity while 22 returned RME and SVE IC50 values of 10.7 ± 4.5 and 99.5 ± 1.7 μM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.

  • 16. Hill, Timothy A
    et al.
    Odell, Luke R
    Quan, Annie
    Abagyan, Ruben
    Ferguson, Gemma
    Robinson, Phillip J
    McCluskey, Adam
    Long chain amines and long chain ammonium salts as novel inhibitors of dynamin GTPase activity.2004In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 14, no 12Article in journal (Refereed)
    Abstract [en]

    We examined a number of ligands with the view of inhibiting the GTPase activity of dynamin. Dynamin contains a pleckstrin homology (PH) domain that interacts with lipids. We report a series of simple lipid-like molecules that display moderate inhibitory activity. Inhibitory activity is linked to chain length and quaternarization of the terminal amine. A change in the counterion, Cl versus Br or I, had little effect on potency. However, introduction of a hydrophobic collar proximal to the charged site was beneficial to dynamin GTPase inhibitory action. The most potent compound was myristoyl trimethyl ammonium bromide (MTMAB, IC(50) 3.15 microM).

  • 17. Hill, Timothy
    et al.
    Odell, Luke R
    Edwards, Jennifer K
    Graham, Mark E
    McGeachie, Andrew B
    Rusak, Jenny
    Quan, Annie
    Abagyan, Ruben
    Scott, Janet L
    Robinson, Phillip J
    McCluskey, Adam
    Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins.2005In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 24Article in journal (Refereed)
    Abstract [en]

    Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a microM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 microM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low microM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50= 5.1 +/- 0.6 microM), its 3,4,5-trihydroxy congener (10) (IC50= 1.7 +/- 0.2 microM), and the corresponding 3-methyl ether (11) (IC50= 9 +/- 3 microM). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50's of 1.7 +/- 0.2, 1.7 +/- 0.2, and 5 +/- 1 microM, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50's of 42 +/- 3, 38 +/- 2, and 61 +/- 2 microM, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.

  • 18.
    Lagerlund, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Mowbray, Sherry L.
    Nilsson, Mikael T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Krajewski, Wojciech
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Nordqvist, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase2007In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 10, no 9, p. 783-789Article in journal (Refereed)
    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.

  • 19. Lehmann, Fredrik
    et al.
    Koolmeister, Tobias
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Scobie, Martin
    A versatile new synthetic route to 1N-hydroxyindazoles2009In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 11, no 21, p. 5078-5081Article in journal (Refereed)
    Abstract [en]

    A new and versatile cyclization reaction affording rare 1N-hydroxyindazoles is presented. Treatment of 2-nitrobenzylamines with methanolic sodium hydroxide furnishes 1N-hydroxyindazoles regioselectively and in high yield. The reaction tolerates a range of functional groups and electronic effects.

  • 20. MacGregor, Kylie A
    et al.
    Abdel-Hamid, Mohammed K
    Odell, Luke R
    Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
    Chau, Ngoc
    Whiting, Ainslie
    Robinson, Phillip J
    McCluskey, Adam
    Development of quinone analogues as dynamin GTPase inhibitors2014In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 85, p. 191-206Article in journal (Refereed)
    Abstract [en]

    Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.

  • 21.
    Mane, Rajendra S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nordeman, Patrik
    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.
    Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide2013In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, no 50, p. 6912-6915Article in journal (Refereed)
    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.

  • 22. McCluskey, Adam
    et al.
    Leitch, Sarah K.
    Garner, James
    Caden, Christine E.
    Hill, Timothy A.
    Odell, Luke R.
    Stewart, Scott G.
    BiCl3-mediated opening of epoxides, a facile route to chlorohydrins or amino alcohols: one reagent, two paths2005In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 46, no 47, p. 8229-8232Article in journal (Refereed)
  • 23. McGeachie, Andrew B
    et al.
    Odell, Luke R
    Centre for Chemical Biology, Chemistry, The University of Newcastle, Callaghan, NSW 2308, Australia.
    Quan, Annie
    Daniel, James A
    Chau, Ngoc
    Hill, Timothy A
    Gorgani, Nick N
    Keating, Damien J
    Cousin, Michael A
    van Dam, Ellen M
    Mariana, Anna
    Whiting, Ainslie
    Perera, Swetha
    Novelle, Aimee
    Young, Kelly A
    Deane, Fiona M
    Gilbert, Jayne
    Sakoff, Jennette A
    Chircop, Megan
    McCluskey, Adam
    Robinson, Phillip J
    Pyrimidyn Compounds: Dual-Action Small Molecule Pyrimidine-Based Dynamin Inhibitors2013In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 7, p. 1507-1518Article in journal (Refereed)
    Abstract [en]

    Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization. We have designed a series of novel pyrimidine-based "Pyrimidyn" compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency. The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 μM for dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date. We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin. The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin. Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals. Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation. This dual mode of action provides an important new tool for molecular dissection of dynamin's role in endocytosis.

  • 24.
    Motwani, Hitesh V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    De Rosa, Maria
    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.
    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.
    Aspartic protease inhibitors containing tertiary alcohol transition-state mimics2014In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 90, p. 462-490Article, review/survey (Refereed)
    Abstract [en]

    Aspartic proteases (APs) are a class of enzymes engaged in the proteolytic digestion of peptide substrates. APs play important roles in physiological and infectious pathways, making them plausible drug targets. For instance in the treatment of HIV infections, access to an efficient combination of protease and reverse transcriptase inhibitors have changed a terminal illness to a chronic but manageable disease. However, the benefits have been limited due to the emergence of drug resistant viral strains, poor pharmacokinetic properties of peptidomimetic inhibitors and adverse effects associated with the treatment. In the 1980s, D. Rich and co-workers proposed a novel strategy for the development of AP inhibitors by replacing the secondary hydroxyl group with a tertiary alcohol as part of the transition state (TS) mimicking moiety. This strategy has been extensively explored over the last decade with a common belief that masking of the polar group, e.g. by intramolecular hydrogen bonding, has the potential to enhance transcellular transport. This is the first review presenting the advances of AP inhibitors comprising a tertiary hydroxyl group. The inhibitors have been classified into different tert-hydroxy TS mimics and their design strategies, synthesis, biological activities, structure-activity-relationships and X-ray structures are discussed.

  • 25.
    Mowbray, Sherry L
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kathiravan, Muthu K
    Pandey, Abhishek A
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, p. 13161-13176Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

  • 26.
    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.

  • 27.
    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.

  • 28.
    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.

  • 29.
    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.

  • 30.
    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.

  • 31.
    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, Structural Molecular Biology.
    Röttger, Svenja
    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.
    Krajewski, Wojciech W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Andersson, C. Evalena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mowbray, Sherry L.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Evaluation of the amino acid binding site of Mycobacterium tuberculosis glutamine synthetase for drug discovery2008In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 10, p. 5501-5513Article in journal (Refereed)
    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.

  • 32. Odell, Adam F
    et al.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Askham, Jon M
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ponnambalam, Sreenivasan
    Hollstein, Monica
    A Novel p53 Mutant Found in Iatrogenic Urothelial Cancers Is Dysfunctional and Can Be Rescued by a Second-site Global Suppressor Mutation2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 23, p. 16704-16714Article in journal (Refereed)
    Abstract [en]

    Exposure to herbal remedies containing the carcinogen aristolochic acid (AA) has been widespread in some regions of the world. Rare A→T TP53 mutations were recently discovered in AA-associated urothelial cancers. The near absence of these mutations among all other sequenced human tumors suggests that they could be biologically silent. There are no cell banks with established lines derived from human tumors with which to explore the influence of the novel mutants on p53 function and cellular behavior. To investigate their impact, we generated isogenic mutant clones by integrase-mediated cassette exchange at the p53 locus of platform (null) murine embryonic fibroblasts and kidney epithelial cells. Common tumor mutants (R248W, R273C) were compared with the AA-associated mutants N131Y, R249W, and Q104L. Assays of cell proliferation, migration, growth in soft agar, apoptosis, senescence, and gene expression revealed contrasting outcomes on cellular behavior following introduction of N131Y or Q104L. The N131Y mutant demonstrated a phenotype akin to common tumor mutants, whereas Q104L clone behavior resembled that of cells with wild-type p53. Wild-type p53 responses were restored in double-mutant cells harboring N131Y and N239Y, a second-site rescue mutation, suggesting that pharmaceutical reactivation of p53 function in tumors expressing N131Y could have therapeutic benefit. N131Y is likely to contribute directly to tumor phenotype and is a promising candidate biomarker of AA exposure and disease. Rare mutations thus do not necessarily point to sites where amino acid exchanges are phenotypically neutral. Encounter with mutagenic insults targeting cryptic sites can reveal specific signature hotspots.

  • 33. Odell, L. R.
    et al.
    Sävmarker, J.
    Lindh, J.
    Nilsson, P.
    Larhed, M.
    7.18 Addition Reactions with Formation of Carbon–Carbon Bonds: (v) The Oxidative Heck Reaction2014In: Comprehensive Organic Synthesis II (Second Edition), Amsterdam: Elsevier, 2014, p. 492-537Chapter in book (Refereed)
    Abstract [en]

    Abstract The Heck reaction, generally defined as the substitution of a vinylic hydrogen with an aryl, vinyl, or benzyl group, is widely regarded as one of the premier synthetic tools for the construction of new C–C bonds. The oxidative Heck reaction, which commences with the generation of the key arylpalladium species under palladium(II) catalysis, has emerged as a powerful alternative to the palladium(0)-catalyzed Mizoroki−Heck reaction over the past decade. This chapter gives an overview of the various olefin and aryl/vinyl substrate classes that have been utilized in this reaction. The material is organized according to the reaction type (inter- or intramolecular), the electronic nature of the olefin (electron-poor, electron-rich, or neutral), and the olefin coupling partner. Special emphasis is given to some of the more recent advances in this area and, where applicable, a critical review of the most synthetically useful methods is presented.

  • 34.
    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.

  • 35.
    Odell, Luke R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Chau, Ngoc
    Mariana, Anna
    Graham, Mark E
    Robinson, Phillip J
    McCluskey, Adam
    Azido and diazarinyl analogues of bis-tyrphostin as asymmetrical inhibitors of dynamin GTPase2009In: ChemMedChem, ISSN 1860-7179, Vol. 4, no 7, p. 1182-1188Article in journal (Refereed)
    Abstract [en]

    Probing the dynamin binding site: Bis-tyrphostin (1, Bis-T), is a potent inhibitor of the phospholipid-stimulated GTPase activity of dynamin I. Analogues of Bis-T have significant potential as a biological probes for the dissection of endocytic pathways. Bis-T-derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues (23 and 24) represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibition.Two azidobenzyl amide (4 and 23) and one 3-trifluoromethyl-3H-diazirin-3-ylphenyl (24) analogues of bis-tyrphostin (1, Bis-T) were synthesised as potential photoaffinity labels for the elucidation of the binding site of compound 1 in dynamin I. Of the two azidobenzyl amide analogues (4 and 23), the terminally substituted 23 retained dynamin I GTPase inhibition (IC(50)=6.4+/-2.8 microM) whilst 4, which was substituted on the central carbon of the amide linker, displayed no activity. Analogue 24 also retained inhibitory activity (IC(50)=36+/-9 microM). Photoaffinity labelling experiments did not unequivocally elucidate the binding pocket of compound 1. However, compounds 23 and 24 represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibitory activity, providing a new direction for analogue synthesis.

  • 36.
    Odell, Luke R
    et al.
    Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
    Howan, Dian
    Gordon, Christopher P.
    Robertson, Mark J.
    Chau, Ngoc
    Mariana, Anna
    Whiting, Ainslie E.
    Abagyan, Ruben
    Daniel, James A.
    Gorgani, Nick N.
    Robinson, Phillip J.
    McCluskey, Adam
    The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 14, p. 5267-5280Article in journal (Refereed)
    Abstract [en]

    We report the development of a homology model for the GTP binding domain of human dynamin I based on the corresponding crystal structure of Dictyostelium discoidum dynamin A. Virtual screening identified 2-[(2-biphenyl-2-yl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonyl)amino]-4-chlorobenzoic acid (1) as a 170 μM potent inhibitor. Homology modeling- and focused library-led synthesis resulted in development of a series of active compounds (the “pthaladyns”) with 4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid (29), a 4.58 ± 0.06 μM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II (5−10 fold). Only pthaladyn-23 (dynamin I IC50 17.4 ± 5.8 μM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC50 of 12.9 ± 5.9 μM. This compound was also competitive with respect to Mg2+·GTP. Thus the pthaladyns are the first GTP competitive inhibitors of dynamin I and II GTPase and may be effective new tools for the study of neuronal endocytosis.

  • 37.
    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-accelerated homogenous catalysis in water2009In: Handbook of green chemistry: Green Catalysis / [ed] edited by Paul T. Anastas, volume editor, Robert H. Crabtree, Weinheim: Wiley-VCH Verlagsgesellschaft, 2009, 1, p. 79-99Chapter in book (Other academic)
  • 38.
    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)
  • 39.
    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)
  • 40.
    Odell, Luke R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. ORGFARM.
    Gustafsson, Tomas
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids2010In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 12, p. 2270-2274Article in journal (Refereed)
    Abstract [en]

    Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.

  • 41. Odell, Luke R.
    et al.
    McCluskey, Adam
    Failes, Timothy W.
    Tiekink, Edward R. T.
    Crystal and Molecular Structures of Benzyl-(2-chloro-6-methylpyrimidin-4-yl)amine and Benzyl-(4-chloro-6-methylpyrimidin-2-yl)amine: Confirmation of Computationally Predicted Restricted Rotation2007In: Journal of Chemical Crystallography, ISSN 1074-1542, E-ISSN 1572-8854, Vol. 37, no 12, p. 817-824Article in journal (Refereed)
    Abstract [en]

    Crystal structures for the isomeric compounds benzyl-(2-chloro-6-methylpyrimidin-4-yl)amine (1), as its hemi-hydrate, and benzyl-(4-chloro-6-methylpyrimidin-2-yl)amine (2) have been determined. Conformational differences lead to multiple molecules, i.e. two and three, in their respective structures. Layers feature in each of the crystal structures and are stabilized by substantial hydrogen-bonding interactions. Compound (1) crystallizes as a hemi-hydrate in the triclinic space group P-1 with a = 8.667(5) Å, b = 11.421(7) Å, c = 12.954(8) Å, α = 78.330(10)°, β = 84.553(10)°, γ = 75.510(9)°, and Z = 4. Compound (2) crystallizes in the monoclinic space group P21/c with a = 10.740(3) Å, b = 21.487(6) Å, c = 14.914(4) Å, β = 95.014(5)°, and Z = 12.

  • 42.
    Odell, Luke R.
    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.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    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.
    Nordqvist, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors2009In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, no 16, p. 4790-4793Article in journal (Refereed)
    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.

  • 43.
    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.

  • 44. Odell, Luke R
    et al.
    Skopec, Jana
    McCluskey, Adam
    A 'cold synthesis' of heroin and implications in heroin signature analysis utility of trifluoroacetic/acetic anhydride in the acetylation of morphine.2006In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 164, no 2-3Article in journal (Refereed)
    Abstract [en]

    Treatment of morphine, at room temperature, with a mixture of trifluoroacetic anhydride (TFAA) and acetic acid (20-30min) affords good yields of heroin. GC-MS and HPLC examination shows that heroin produced by this route to be extremely clean, but the product contains slightly less heroin than observed via the more traditional acetic anhydride (AA) route (76.1% versus 83.55%); and greater quantities of 3-MAM and 6-MAM (6.9% versus 0.75% and 7.13% versus 0.63%). The concentration ratios of the major alkaloid impurities were found to be both production method (TFAA and AA) as well as morphine extraction methodology dependant. Data contained herein describe the impact of this new production method on current intelligence efforts, largely by-passing existing heroin signature programs and the UNDCP's efforts to restrict access to key synthetic precursors. Given the methodology dependency we find that examination of the major alkaloid ratios is unsuitable for the development of a new heroin signature program. Further examination of the TFAA methodology allowed the identification of TFAA specific marker compounds, namely bis-trifluoroacetylmorphine (30), 3-trifluoroacetyl-6-acetylmorphine (31), 3-acetyl-6-trifluoroacetylmorphine (32) and trifluoroacetylcodeine (33). However, the hydrolytic lability of trifluroacetyl esters requires careful treatment of suspect samples, thus we propose a modification to existing HSP's in instances were the 6-MAM/WM ratio falls within the average minimum and maximum values of 6.17 and 17.32.

  • 45. Odell, Luke R
    et al.
    Skopec, Jana
    McCluskey, Adam
    Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N. Implications for the identification of illicit heroin of Tasmanian origin.2008In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 175, no 2-3Article in journal (Refereed)
    Abstract [en]

    Tasmanian opium accounts for 25% of the world's legal supply of opium straw, and in 1998-99 sufficient numbers of flower pods (66,013) to manufacture ca 500 kg of heroin were stolen. Whilst the heroin signature program has been developed to determine the origin of heroin from other key producers, no such signature currently exists for Tasmanian derived heroin. Tasmanian poppies contain a unique alkaloid, oripavine, which is the source of 'marker' impurities in illicit heroin produced from Tasmanian poppy straw. Treatment of oripavine (500mg) under Thiboumery and Mohr heroin processing conditions, followed by simple evaporative workup afforded 613 mg of a dark orange residue, which upon extensive chromatographic purification yielded oripavine 3-acetate (2) 22 mg; 3-acetyl-N-acetyldesthebaine (3) 35 mg; 3-acetyl-6-methoxy-4,5-epoxyphenanthrene (4) 5.8 mg; 3,4-diacetyl-6-methoxyphenanthrene (5) 27 mg; and 3,4,6-methoxy-5-[2(N-methylacetamido)]ethylphenanthrene (6) 52 mg. Compounds (2-6) are derived from oripavine and are unique to heroin derived from the Tasmanian poppy Papaver somniferum N. Analysis of illicit heroin samples seized from Turkey, Pakistan, Columbia and Myanmar did not reveal any of the aforementioned marker compounds. We have, however, identified four of these marker compounds (3-6) in seized heroin samples from Australia suggesting that they are of Tasmanian origin. Complete details of the isolation and identification of these compounds are provided.

  • 46.
    Odell, Luke R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    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-promoted aminocarbonylation of aryl triflates using Mo(CO)(6) as a solid CO source2008In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 42, p. 6115-6118Article in journal (Refereed)
    Abstract [en]

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

  • 47.
    Roslin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    De Rosa, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Deuther-Conrad, Winnie
    Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, 04318 Leipzig, Germany.
    Eriksson, Jonas
    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.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Brust, Peter
    Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, 04318 Leipzig, Germany.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and In Vitro Evaluation of 5-Substituted Benzovesamicol Analogs containing N-Substituted Amides as Potential Positron Emission Tomography Tracers for the Vesicular Acetylcholine Transporter2017In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 19, p. 5095-5106Article in journal (Refereed)
    Abstract [en]

    Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (+/-)-7i and (+/-)-7l had the highest affinities for VAChT. Compound (+/-)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the sigma(1) and sigma(2) receptors. Enantiomeric resolution gave (+/-)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (+/-)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7 nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [C-11]-(+/-)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved C-11-labelled VAChT PET tracers.

  • 48.
    Roslin, Sara
    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.
    Palladium and Visible-Light Mediated Carbonylative Suzuki-Miyaura Coupling of Unactivated Alkyl Halides and Aryl Boronic Acids2017In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 53, p. 6895-6898Article in journal (Refereed)
    Abstract [en]

    Herein, a simple and efficient method for the palladium-catalyzed carbonylation of aryl boronic acids with unactivated alkyl iodides and bromides under visible-light irradiation, ambient temperature and low CO-pressure is presented. Notably, the procedure uses readily available equipment and an inexpensive palladium catalyst to generate the key alkyl radical intermediate. These mild conditions enabled the synthesis of a range of functionalized aryl alkyl ketones including the antipsychotic drug, melperone.

  • 49.
    Roslin, Sara
    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.
    Visible-Light Photocatalysis as an Enabling Tool for the Functionalization of Unactivated C(sp(3))-Substrates2017In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2017, no 15, p. 1993-2007Article, review/survey (Refereed)
    Abstract [en]

    Over the past decade, visible-light photocatalysis has emerged as one of the brightest and most dynamic fields in modern organic chemistry. By employing a transition-metal- or organic-dye-based photocatalyst in conjunction with a low-energy visible-light source, this synthetic manifold allows the facile generation of radical intermediates that can subsequently be directed through a wide range of transformations. Although initial studies focused largely on the functionalization of stabilized radical intermediates, over the past few years significant efforts have been directed towards the functionalization of challenging unactivated radical precursors. In this review we summarize the recent developments in the use of visible-light photocatalysis for the functionalization of unactivated C(sp(3))-substrates.

  • 50.
    Russo, Francesco
    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.
    Olofsson, Kristofer
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-Heated Transition Metal-Catalyzed Coupling Reactions2012In: Microwaves in Organic Synthesis / [ed] de la Hoz, A, Loupy, A, Weinheim: Wiley-VCH Verlagsgesellschaft, 2012, 3, p. 607-672Chapter in book (Refereed)
12 1 - 50 of 76
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