دورية أكاديمية
أعرض في EDS

Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA).

التفاصيل البيبلوغرافية
العنوان: Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA).
المؤلفون: Igual MO; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, 14040-930, Ribeirão Preto, Brazil., Nunes PSG; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, 14040-930, Ribeirão Preto, Brazil., da Costa RM; Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, 14049-900, Ribeirão Preto, Brazil., Mantoani SP; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, 14040-930, Ribeirão Preto, Brazil., Tostes RC; Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, 14049-900, Ribeirão Preto, Brazil., Carvalho I; School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, Monte Alegre, 14040-930, Ribeirão Preto, Brazil. Electronic address: ivone.carvalho@pq.cnpq.br.
المصدر: Carbohydrate research [Carbohydr Res] 2019 Jan 01; Vol. 471, pp. 43-55. Date of Electronic Publication: 2018 Oct 26.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0043535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-426X (Electronic) Linking ISSN: 00086215 NLM ISO Abbreviation: Carbohydr Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: Amsterdam.
مواضيع طبية MeSH: Enzyme Inhibitors/*chemical synthesis , Triazoles/*chemical synthesis , beta-N-Acetylhexosaminidases/*antagonists & inhibitors, Animals ; Cell Survival/drug effects ; Cells, Cultured ; Cycloaddition Reaction ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Molecular Docking Simulation ; Molecular Structure ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Myocytes, Smooth Muscle/cytology ; Myocytes, Smooth Muscle/drug effects ; Rats ; Structure-Activity Relationship ; Triazoles/chemistry ; Triazoles/pharmacology
مستخلص: O-GlcNAcylation or O-GlcNAc modification is a post-translational modification of several proteins responsible for fundamental cellular processes. Dysregulation of the O-GlcNAc pathway has been linked to the etiology of several diseases such as neurodegenerative and cardiovascular diseases, type 2 diabetes and cancer. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from the modified proteins and several carbohydrate-based OGA inhibitors have been synthesized to understand the role of O-GlcNAc-modified proteins in physiological and pathological conditions. However, many of the inhibitors lack selectivity for OGA over lysosomal hexosaminidases A and B. Aiming the selectively inhibition of OGA, we propose herein the synthesis of twelve novel glucopyranoside derivatives exploring the bioisosteric replacement of the GlcNAc 2-acetamide group by 1,4-disubstituted 1,2,3-triazole ring, bearing a variety of central chains with different shapes. Compounds were readily prepared through "Copper(I) Catalyzed Azide/Alkyne Cycloaddition" (CuAAC) reaction between a sugar azide and different terminal alkynes. Initial Western Blot analyses and further inhibitory assays proved that compounds 6a (IC 50  = 0.50 ± 0.02 μM, OGA), 6k (IC 50  = 0.52 ± 0.01 μM, OGA) and 6l (IC 50  = 0.72 ± 0.02 μM, OGA) were the most potent and selective compounds of the series. Structure-activity relationship analyses and molecular docking simulations demonstrated that the bridge of two-carbon atoms between the C-4 position of the triazole and the phenyl ring (6a), which may be replaced by heteroatoms such as N (6k) or O (6l), is fundamental for accommodation and inhibition within OGA catalytic pocket.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: 1,2,3-Triazole; Click chemistry; O-GlcNAcase; O-GlcNAcylation; Selective inhibitors
المشرفين على المادة: 0 (Enzyme Inhibitors)
0 (Triazoles)
EC 3.2.1.50 (hexosaminidase C)
EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
تواريخ الأحداث: Date Created: 20181110 Date Completed: 20190415 Latest Revision: 20190415
رمز التحديث: 20221213
DOI: 10.1016/j.carres.2018.10.007
PMID: 30412832
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-426X
DOI:10.1016/j.carres.2018.10.007