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1.
  • Berglund, P., et al. (författare)
  • Altering the specificity of subtilisin B. lentus by combining site-directed mutagenesis and chemical modification
  • 1996
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - 0960-894X .- 1464-3405. ; 6:21, s. 2507-2512
  • Tidskriftsartikel (refereegranskat)abstract
    • The thiol side chain of the M222C mutant of the subtilisin from Bacillus lentus (SBL) has been chemically modified by methyl-, aminoethyl-, and sulfonatoethylthiosulfonate reagents. Introduction of charged residues into the active site of the enzyme reduced the catalytic efficiency with Suc-AAPF-pNA as the substrate, but resulted in better binding of sterically demanding boronic acid inhibitors.
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2.
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3.
  • Jönsson, Christina, et al. (författare)
  • Immobilized oxazoline-containing ligands in asymmetric catalysis - A review
  • 2002
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - 0960-894X .- 1464-3405. ; 12:14, s. 1857-1861
  • Forskningsöversikt (refereegranskat)abstract
    • Metal complexes of chiral oxazoline derivatives immobilized on soluble as well as insoluble supports serve as versatile asymmetric catalysts in a variety of applications. In a few cases recovery and reuse of the chiral ligands have been achieved.
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4.
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5.
  • Barlind, Jonas G., et al. (författare)
  • Identification and design of a novel series of MGAT2 inhibitors
  • 2013
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2721-2726
  • Tidskriftsartikel (refereegranskat)abstract
    • [Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naive, p < 0.01) in plasma triacylglycerol (TAG) concentration.
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6.
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7.
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8.
  • Carta, Fabrizio, et al. (författare)
  • Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c
  • 2009
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:23, s. 6649-6654
  • Tidskriftsartikel (refereegranskat)abstract
    • The Rv3588c gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO2 hydration (k(cat) of 9.8 x 10(5) s(-1), and k(cat)/K-m of 9.3 x 10(7) M-1 s(1)) among the three beta-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K(I)s of 9-59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action.
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9.
  • Chen, Zhen, et al. (författare)
  • Synthesis and preliminary evaluation of a novel positron emission tomography (PET) ligand for imaging fatty acid amide hydrolase (FAAH)
  • 2020
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 30:21
  • Tidskriftsartikel (refereegranskat)abstract
    • Fatty acid amide hydrolase (FAAH) exerts its main function in the catabolism of the endogenous chemical messenger anandamide (AEA), thus modulating the endocannabinoid (eCB) pathway. Inhibition of FAAH may serve as an effective strategy to relieve anxiety and possibly other central nervous system (CNS)-related disorders. Positron emission tomography (PET) would facilitate us to better understand the relationship between FAAH in certain disease conditions, and accelerate clinical translation of FAAH inhibitors by providing in vivo quantitative information. So far, most PET tracers show irreversible binding patterns with FAAH, which would result in complicated quantitative processes. Herein, we have identified a new FAAH inhibitor (1-((1-methyl-1H-indol-2-yl)methyl)piperidin-4-yl)(oxazol-2-yl)methanone (8) which inhibits the hydrolysis of AEA in the brain with high potency (IC50 value 11 nM at a substrate concentration of 0.5 µM), and without showing time-dependency. The PET tracer [11C]8 (also called [11C]FAAH-1906) was successfully radiolabeled with [11C]MeI in 17 ± 6% decay-corrected radiochemical yield (n = 7) with >74.0 GBq/μmol (2 Ci/μmol) molar activity and >99% radiochemical purity. Ex vivo biodistribution and blocking studies of [11C]8 in normal mice were also conducted, indicating good brain penetration, high brain target selectivity, and modest to excellent target selectivity in peripheral tissues. Thus, [11C]8 is a potentially useful PET ligand with enzyme inhibitory and target binding properties consistent with a reversible mode of action.
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10.
  • Cooper, Ian R., et al. (författare)
  • Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors
  • 2016
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 26:17, s. 4179-4183
  • Tidskriftsartikel (refereegranskat)abstract
    • There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.
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11.
  • Courtiol-Legourd, Stephanie, et al. (författare)
  • Synthesis and kinetic evaluation of phosphomimetic inhibitors targeting type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis
  • 2024
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 102
  • Tidskriftsartikel (refereegranskat)abstract
    • Because tuberculosis is still a major health threat worldwide, identification of new drug targets is urgently needed. In this study, we considered type B ribose -5 -phosphate isomerase from Mycobacterium tuberculosis as a potential target, and addressed known problems of previous inhibitors in terms of their sensitivity to hydrolysis catalyzed by phosphatase enzymes, which impaired their potential use as drugs. To this end, we synthesized six novel phosphomimetic compounds designed to be hydrolytically stable analogs of the substrate ribose 5 -phosphate and the best known inhibitor 5-phospho-D-ribonate. The phosphate function was replaced by phosphonomethyl, sulfate, sulfonomethyl, or malonate groups. Inhibition was evaluated on type A and type B ribose -5phosphate isomerases, and stability towards hydrolysis using alkaline phosphatase and veal serum was assessed. One of the phosphomimetic analogs, 5-deoxy-5-phosphonomethyl-D-ribonate, emerged as the first strong and specific inhibitor of the M. tuberculosis enzyme that is resistant to hydrolysis.
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12.
  • Cumpstey, Ian, et al. (författare)
  • Synthesis and alpha-Glucosidase II inhibitory activity of valienamine pseudodisaccharides relevant to N-glycan biosynthesis
  • 2011
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:18, s. 5219-5223
  • Tidskriftsartikel (refereegranskat)abstract
    • Valienol-derived allylic C-1 bromides have been used as carbaglycosyl donors for alpha-xylo configured valienamine pseudodisaccharide synthesis. We synthesised valienamine analogues of the Glc(alpha 1 -> 3)Glc and Glc(alpha 1 -> 3) Man disaccharides representing the linkages cleaved by alpha-Glucosidase II in N-glycan biosynthesis. These (N1 -> 3)-linked pseudodisaccharides were found to have some alpha-Glucosidase II inhibitory activity, while two other (N1 -> 6)-linked valienamine pseudodisaccharides failed to inhibit the enzyme. (C)
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13.
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14.
  • Danielsson, Marie, 1981-, et al. (författare)
  • Pharmacodynamic synergy strictly dependent on the co-operative aggregation of enantiomers of cyclic peptides in the bacterial cell membrane
  • 2011
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:18, s. 5262-5265
  • Tidskriftsartikel (refereegranskat)abstract
    • The antimicrobial activity of the peptide enantiomers cyclo[d-Tle-d-Lys-d-Tle-l-Ala-d-Tle-l-Ala-d-Tle-l-Ala] and cyclo[l-Tle-l-Lys-l-Tle-d-Ala-l-Tle-d-Ala-l-Tle-d-Ala] against Bacillus megaterium was investigated. Both these peptides showed very low activity in both an agar diffusion assay and a broth microdilution assay. However, when both peptides were present during the experiments a potent inhibition with an IC(50) value of 2μM was observed. Furthermore, the peptides also showed low hemolytic activity. Neither peptide had any hemolytic activity in concentrations up to 1mM but when erythrocytes were exposed to both peptides a weak hemolytic activity could be observed with a HC(50) value of 316μM.
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17.
  • Ekblad, Torun, et al. (författare)
  • Positioning of Tc-99m-chelators influences radiolabeling, stability and biodistribution of Affibody molecules
  • 2009
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:14, s. 3912-3914
  • Tidskriftsartikel (refereegranskat)abstract
    • Affibody molecules represent a novel class of affinity proteins with a high potential as tracers for radio-nuclide molecular imaging. In this comparative structure-property study, a series of Affibody molecules with the Tc-99m-chelators maGGG, maSSS, or maESE attached to the e-amine of the internally positioned K49 was prepared by peptide synthesis, for comparison to molecules with similar chelators positioned at the N-terminus. The conjugates were labeled with Tc-99m and evaluated in vitro and in vivo. It was found that both composition and position of the chelating moiety influence the label stability, biodistribution and targeting properties of HER2-binding Affibody molecules.
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18.
  • Enquist, Per-Anders, et al. (författare)
  • Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens
  • 2012
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 22:10, s. 3550-3553
  • Tidskriftsartikel (refereegranskat)abstract
    • Small molecule screening identified 5-nitro-7-((4-phenylpiperazine-1-yl-)methyl)quinolin-8-ol INP1750 as a putative inhibitor of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. In this study we report structure-activity relationships for inhibition of T3S and show that the most potent compounds target both the extracellular bacterium Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis in cell-based infection models.
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19.
  • Gabr, Moustafa, et al. (författare)
  • Discovery of biphenyl pyrazole scaffold for neurodegenerative diseases : A novel class of acetylcholinesterase-centered multitargeted ligands
  • 2020
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0960-894X .- 1464-3405. ; 30:17
  • Tidskriftsartikel (refereegranskat)abstract
    • Multitargeted ligands have demonstrated remarkable efficiency as potential therapeutics for neurodegenerative diseases as they target multiple pathways involved in the progression of these diseases. Herein, we report first-in-class dual inhibitor of acetylcholinesterase (AChE) and tau aggregation as a novel class of multitargeted ligands for neurodegenerative diseases. The reported biphenyl pyrazole scaffold binds monomeric tau with sub-micromolar affinity and impedes the formation of tau oligomers at early stages. Additionally, the lead compound inhibited AChE activity with an IC50 value of 0.35 +/- 0.02 mu M. Remarkably, the neuroprotective effect of this lead in induced cytotoxicity model of SH-SY5Y neuroblastoma cells is superior to single-targeted AChE and tau-aggregation inhibitors. This scaffold would enable development of new generation of multitargeted ligands for neurodegenerative diseases that function through dual targeting of AChE and monomeric tau.
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20.
  • Globisch, Daniel, et al. (författare)
  • Validation of onchocerciasis biomarker N-acetyltyramine-O-glucuronide (NATOG)
  • 2017
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0960-894X .- 1464-3405. ; 27:15, s. 3436-3440
  • Tidskriftsartikel (refereegranskat)abstract
    • The Neglected Tropical Disease onchocerciasis is a parasitic disease. Despite many control programmes by the World Health Organization (WHO), large communities in West and Central Africa are still affected. Besides logistic challenges during biannual mass drug administration, the lack of a robust, point-of-care diagnostic is limiting successful eradication of onchocerciasis. Towards the implementation of a non-invasive and point-of-care diagnostic, we have recently reported the discovery of the biomarker N-acetyltyramine-O-glucuronide (NATOG) in human urine samples using a metabolomics-mining approach. NATOG's biomarker value was enhanced during an investigation in a rodent model. Herein, we further detail the specificity of NATOG in active onchocerciasis infections as well as the co-infecting parasites Loa loa and Mansonella perstans. Our results measured by liquid chromatography coupled with mass spectrometry (LC-MS) reveal elevated NATOG values in mono-and co-infection samples only in the presence of the nematode Onchocerca volvulus. Metabolic pathway investigation of L-tyrosine/tyramine in all investigated nematodes uncovered an important link between the endosymbiotic bacterium Wolbachia and O. volvulus for the biosynthesis of NATOG. Based on these extended studies, we suggest NATOG as a biomarker for tracking active onchocerciasis infections and provide a threshold concentration value of NATOG for future diagnostic tool development.
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21.
  • Hanessian, Stephen, et al. (författare)
  • Design and synthesis of macrocyclic indoles targeting blood coagulation cascade Factor XIa
  • 2010
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier Ltd. - 0960-894X .- 1464-3405. ; 20:23, s. 6925-6928
  • Tidskriftsartikel (refereegranskat)abstract
    • The synthesis of a series of novel macrocyclic compounds designed to target blood coagulation Factor XIa is described. The compounds were evaluated for their inhibition of a small set of serine proteases. Several compounds displayed modest activity and good selectivity for Factor XIa. Within the series, a promising lead structure for developing novel macrocyclic inhibitors of thrombin was identified.
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22.
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24.
  • Hernandez, Frank J, et al. (författare)
  • Aptamers as a model for functional evaluation of LNA and 2′-amino LNA
  • 2009
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Pergamon Press. - 0960-894X .- 1464-3405. ; 19:23, s. 6585-6587
  • Tidskriftsartikel (refereegranskat)abstract
    • The affinity change upon incorporation of LNA and 2′-amino-LNA monomers into an avidin binding DNA aptamer is described. The kinetic profile of selected modified-aptamer was obtained by surface plasmon resonance experiments and compared with the profile of the parent unmodified DNA aptamer. We report significant improvement of avidin binding affinity by the incorporation of single LNA modifications into the aptamer, and successful incorporation of 2′-amino LNA as a novel monomer in aptamers with potential function as carrier unit for additional molecular entities. © 2009 Elsevier Ltd. All rights reserved.
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25.
  • Hill, Timothy A, et al. (författare)
  • Long chain amines and long chain ammonium salts as novel inhibitors of dynamin GTPase activity.
  • 2004
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 14:12
  • Tidskriftsartikel (refereegranskat)abstract
    • 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).
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26.
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27.
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28.
  • Jacobsson, Mårten, et al. (författare)
  • Xylose as a carrier for boron containing compounds
  • 2008
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 18:7, s. 2451-2454
  • Tidskriftsartikel (refereegranskat)abstract
    • A xylosylated carborane was synthesized by standard carbohydrate methodology and tested on normal HFL-1 cells as well as transformed T24 cells. The xylosylated carborane initiated glycosaminoglycan (GAG) synthesis in both cell lines and treatment with the carborane gave a pronounced translocation of proteoglycans to the nuclei of T24 cells. However, most of the boron-containing compounds were secreted to the medium. We conclude that xylosides carrying carboranes are not suitable for boron neutron capture therapy (BNCT) for T24 cells. However, the uptake of boron-containing xyloside, the GAG priming capacity, and the nuclear translocation of glypican-1 make this xyloside a candidate for further investigation for selectivity toward other tumor cell lines.
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29.
  • Jaunsleine, Krista, et al. (författare)
  • Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake – The importance of chirality and ring size of cyclic amines
  • 2024
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - 0960-894X .- 1464-3405. ; 97
  • Tidskriftsartikel (refereegranskat)abstract
    • β2-Adrenergic receptor (β2AR) agonists have been reported to stimulate glucose uptake (GU) by skeletal muscle cells and are therefore highly interesting as a possible treatment for type 2 diabetes (T2D). The chirality of compounds often has a great impact on the activity of β2AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines. For the N-butyl and the N-(2-pentyl) compounds, the (R) and (R,R) (3d and 7e) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (R,R,R) enantiomer of the azetidine (8a) and the pyrrolidine (9a) had the highest activity. Altogether, these results provide pivotal information for designing novel β2AR agonist for the treatment of T2D.
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30.
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31.
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32.
  • Liebens, Veerle R., et al. (författare)
  • Identification and characterization of an anti-pseudomonal dichlorocarbazol derivative displaying anti-biofilm activity
  • 2014
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 24:23, s. 5404-5408
  • Tidskriftsartikel (refereegranskat)abstract
    • Pseudomonas aeruginosa strains resistant towards all currently available antibiotics are increasingly encountered, raising the need for new anti-pseudomonal drugs. We therefore conducted a medium-throughput screen of a small-molecule collection resulting in the identification of the N-alkylated 3,6-dihalogenocarbazol 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol (MIC = 18.5 ?g mL-1). This compound, compound 1, is bacteriostatic towards a broad spectrum of Gram-positive and Gram-negative pathogens, including P. aeruginosa. Importantly, 1 also eradicates mature biofilms of P. aeruginosa. 1 displays no cytotoxicity against various human cell types, pointing to its potential for further development as a novel antibacterial drug.
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33.
  • Lindfors, Lina, et al. (författare)
  • Is GPR146 really the receptor for proinsulin C-peptide?
  • 2020
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 30:13
  • Tidskriftsartikel (refereegranskat)abstract
    • Proinsulin C-peptide has previously been proposed to interact with a G-protein coupled receptor (GPCR), specifically the orphan receptor GPR146. To investigate the potential of C-peptide in treating complications of diabetes, such as kidney damage, it is necessary to understand its mode of action. We used CHO-K1 cells expressing human GPR146 to study human and murine C-peptide in dynamic mass redistribution and GPCR beta-arrestin assays, as well as with fluorescence confocal microscopy. Neither assay revealed any significant intracellular response to C-peptide at concentrations of up to 33 mu M. We observed no internalisation of C-peptide by fluorescence microscopy. Our results do not support GPR146 as the receptor for C-peptide, but suggest that further investigations of the mode of action of C-peptide should be undertaken.
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34.
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35.
  • Llona-Minguez, Sabin, et al. (författare)
  • Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2 : Pyridone- and pyrimidinone-derived systems
  • 2017
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 27:15, s. 3219-3225
  • Tidskriftsartikel (refereegranskat)abstract
    • Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE).
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36.
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37.
  • Macsari, Istvan, et al. (författare)
  • Phenyl isoxazole voltage-gated sodium channel blockers : structure and activity relationship
  • 2011
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:13, s. 3871-3876
  • Tidskriftsartikel (refereegranskat)abstract
    • Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.
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38.
  • Makatini, Maya M., et al. (författare)
  • Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease
  • 2011
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:8, s. 2274-2277
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC50 activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC50) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.
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39.
  • Mittal, Monica, et al. (författare)
  • Kinetic investigation of human 5-lipoxygenase with arachidonic acid
  • 2016
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 26:15, s. 3547-3551
  • Tidskriftsartikel (refereegranskat)abstract
    • Human 5-lipoxygenase (5-LOX) is responsible for the formation of leukotriene (LT)A(4), a pivotal intermediate in the biosynthesis of the leukotrienes, a family of proinflammatory lipid mediators. 5-LOX has thus gained attention as a potential drug target. However, details of the kinetic mechanism of 5-LOX are still obscure. In this Letter, we investigated the kinetic isotope effect (KIE) of 5-LOX with its physiological substrate, arachidonic acid (AA). The observed KIE is 20 +/- 4 on k(cat) and 17 +/- 2 on k(cat)/K-M at 25 degrees C indicating a non-classical reaction mechanism. The observed rates show slight temperature dependence at ambient temperatures ranging from 4 to 35 degrees C. Also, we observed low Arrhenius prefactor ratio (A(H)/A(D) = 0.21) and a small change in activation energy (E-a(D) - E-a(H) = 3.6 J/mol) which suggests that 5-LOX catalysis involves tunneling as a mechanism of H-transfer. The measured KIE for 5-LOX involves a change in regioselectivity in response to deuteration at position C7, resulting in H-abstraction form C10 and formation of 8-HETE. The viscosity experiments influence the (H)k(cat), but not (D)k(cat). However the overall kcat/K-M is not affected for labeled or unlabeled AA, suggesting that either the product release or conformational rearrangement might be involved in dictating kinetics of 5-LOX at saturating conditions. Investigation of available crystal structures suggests the role of active site residues (F421, Q363 and L368) in regulating the donor-acceptor distances, thus affecting H-transfer as well as regiospecificity. In summary, our study shows that that the H-abstraction is the rate limiting step for 5-LOX and that the observed KIE of 5-LOX is masked by a change in regioselectivity.
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40.
  • Muthusamy, Karen, et al. (författare)
  • Design and study of peptide-based inhibitors of amylin cytotoxicity
  • 2010
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 20:4, s. 1360-1362
  • Tidskriftsartikel (refereegranskat)abstract
    • The incidence of type II diabetes is on the increase each year and the World Health Organisation (WHO) predicts there to be over 360 million diabetic patients worldwide by the year 2030. Deposits consisting mainly of a small protein, called islet amyloid polypeptide (amylin), which aggregates into oligo-/polymeric beta sheet structures is responsible for cytoxicity to the pancreatic beta-cells, thus inhibition of this process has been explored as a potential prevention or treatment. N-Methylated and non N-methylated peptides spanning the length of amylin(1-37) were synthesised and evaluated for their inhibition of full length amylin mediated cytoxicity to RIN-5F cells. The non N-methylated peptides were very effective in inhibiting the cytotoxicity while the N-methylated peptides were not. Both the N-methylated and non N-methylated versions of the 29-34 region were equally effective.
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41.
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42.
  • Nilsson, Magnus, et al. (författare)
  • Discovery of 4 '-azido-2 '-deoxy-2 '-C-methyl cytidine and prodrugs thereof : A potent inhibitor of Hepatitis C virus replication
  • 2012
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 22:9, s. 3265-3268
  • Tidskriftsartikel (refereegranskat)abstract
    • 4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC50 value of 1.2 mu M and showing moderate in vivo bioavailability in rat (F = 14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof. (C) 2012 Elsevier Ltd. All rights reserved.
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43.
  • Nilsson, Magnus, et al. (författare)
  • Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease : Exploration of P2 quinazoline substituents
  • 2010
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 20:14, s. 4004-4011
  • Tidskriftsartikel (refereegranskat)abstract
    • Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.
  •  
44.
  • Odell, Luke R., et al. (författare)
  • Functionalized 3-amino-imidazo[1,2-a]pyridines : A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
  • 2009
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:16, s. 4790-4793
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  •  
45.
  • Pei, Zhichao, et al. (författare)
  • Redox-Responsive and Calcium-Dependent Switching of Glycosyldisulfide Interactions with Concanavalin A
  • 2005
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 15, s. 2707-2710
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycosyldisulfides can interact efficiently with carbohydrate-binding entities. This has been shown for a range of thiosaccharide dimers when tested for their effects against the lectin Concanavalin A using a modified quartz crystal microbalance-technique. Contrary to the thiosaccharide monomers, showing no significant binding up to 10 mM, several of the dimers showed IC50-values in the low millimolar range. Three of the glycosyldisulfides tested also displayed very high positive apparent cooperativity effects that were found to be both calcium-dependent and redox-responsive.
  •  
46.
  • Pelcman, Benjamin, et al. (författare)
  • 3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15-lipoxygenase-1
  • 2015
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 25:15, s. 3024-3029
  • Tidskriftsartikel (refereegranskat)abstract
    • Investigation of 1N-substituted pyrazole-3-carboxanilides as 15-lipoxygenase-1 (15-LOX-1) inhibitors demonstrated that the 1N-substituent was not essential for activity or selectivity. Additional halogen substituents on the pyrazole ring, however, increased activity. Further development led to triazole-4-carboxanilides and 2-(3-pyrazolyl) benzoxazoles, which are potent and selective 15-LOX-1 inhibitors.
  •  
47.
  • Pelcman, Benjamin, et al. (författare)
  • N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase
  • 2015
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 25:15, s. 3017-3023
  • Tidskriftsartikel (refereegranskat)abstract
    • High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.
  •  
48.
  • Petrelli, Riccardo, et al. (författare)
  • From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase : Synthesis and biological evaluation of valproic esters of 3'-C-methyladenosine
  • 2014
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 24:22, s. 5304-5309
  • Tidskriftsartikel (refereegranskat)abstract
    • We synthesized a series of serum-stable covalently linked drugs derived from 3'-C-methyladenosine (3'-Me-Ado) and valproic acid (VPA), which are ribonucleotide reductase (RR) and histone deacetylase (HDAC) inhibitors, respectively. While the combination of free VPA and 3'-Me-Ado resulted in a clear synergistic apoptotic effect, the conjugates had lost their HDAC inhibitory effect as well as the corresponding apoptotic activity. Two of the analogs, 2',5'-bis-O-valproyl-3'-C-methyladenosine (A160) and 5'-O-valproyl-3'-C-methyladenosine (A167), showed promising cytotoxic activities against human hematological and solid cancer cell lines. A167 was less potent than A160 but had interesting features as an RR inhibitor. It inhibited RR activity by competing with ATP as an allosteric effector and concomitantly reduced the intracellular deoxyribonucleoside triphosphate (dNTP) pools. A167 represents a novel lead compound, which in contrast to previously used RR nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases.
  •  
49.
  • Sabbani, Sunil, et al. (författare)
  • Piperidine dispiro-1,2,4-trioxane analogues
  • 2008
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 18:21, s. 5804-5808
  • Tidskriftsartikel (refereegranskat)abstract
    • Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)(2) catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting beta-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity.  
  •  
50.
  • Sallander, Jessica, et al. (författare)
  • Structural determinants of subtype selectivity and functional activity of angiotensin II receptors
  • 2016
  • Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 26:4, s. 1355-1359
  • Tidskriftsartikel (refereegranskat)abstract
    • Agonists of the angiotensin II receptor type 2 (AT(2)), a G-protein coupled receptor, promote tissue protective effects in cardiovascular and renal diseases, while antagonists reduce neuropathic pain. We here report detailed molecular models that explain the AT(2) receptor selectivity of our recent series of non-peptide ligands. In addition, minor structural changes of these ligands that provoke different functional activity are rationalized at a molecular level, and related to the selectivity for the different receptor conformations. These findings should pave the way to structure based drug discovery of AT(2) receptor ligands.
  •  
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