| 1. |
- Berglund, P., et al.
(författare)
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Altering the specificity of subtilisin B. lentus by combining site-directed mutagenesis and chemical modification
- 1996
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - 0960-894X .- 1464-3405. ; 6:21, s. 2507-2512
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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)
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Immobilized oxazoline-containing ligands in asymmetric catalysis - A review
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - 0960-894X .- 1464-3405. ; 12:14, s. 1857-1861
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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)
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Identification and design of a novel series of MGAT2 inhibitors
- 2013
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 23:9, s. 2721-2726
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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)
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Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:23, s. 6649-6654
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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)
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Synthesis and preliminary evaluation of a novel positron emission tomography (PET) ligand for imaging fatty acid amide hydrolase (FAAH)
- 2020
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 30:21
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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)
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Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors
- 2016
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 26:17, s. 4179-4183
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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)
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Synthesis and kinetic evaluation of phosphomimetic inhibitors targeting type B ribose-5-phosphate isomerase from Mycobacterium tuberculosis
- 2024
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 102
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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)
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Synthesis and alpha-Glucosidase II inhibitory activity of valienamine pseudodisaccharides relevant to N-glycan biosynthesis
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:18, s. 5219-5223
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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)
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Pharmacodynamic synergy strictly dependent on the co-operative aggregation of enantiomers of cyclic peptides in the bacterial cell membrane
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 21:18, s. 5262-5265
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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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| 15. |
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| 16. |
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| 17. |
- Ekblad, Torun, et al.
(författare)
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Positioning of Tc-99m-chelators influences radiolabeling, stability and biodistribution of Affibody molecules
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 19:14, s. 3912-3914
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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)
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Derivatives of 8-hydroxyquinoline-antibacterial agents that target intra- and extracellular Gram-negative pathogens
- 2012
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier. - 0960-894X .- 1464-3405. ; 22:10, s. 3550-3553
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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)
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Discovery of biphenyl pyrazole scaffold for neurodegenerative diseases : A novel class of acetylcholinesterase-centered multitargeted ligands
- 2020
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0960-894X .- 1464-3405. ; 30:17
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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)
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Validation of onchocerciasis biomarker N-acetyltyramine-O-glucuronide (NATOG)
- 2017
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0960-894X .- 1464-3405. ; 27:15, s. 3436-3440
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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)
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Design and synthesis of macrocyclic indoles targeting blood coagulation cascade Factor XIa
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier Ltd. - 0960-894X .- 1464-3405. ; 20:23, s. 6925-6928
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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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| 23. |
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| 24. |
- Hernandez, Frank J, et al.
(författare)
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Aptamers as a model for functional evaluation of LNA and 2′-amino LNA
- 2009
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Pergamon Press. - 0960-894X .- 1464-3405. ; 19:23, s. 6585-6587
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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)
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Long chain amines and long chain ammonium salts as novel inhibitors of dynamin GTPase activity.
- 2004
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 14:12
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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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