'Click chemistry' synthesis of 1-(α-d-mannopyranosyl)-1, 2, 3-triazoles for inhibition of α-mannosidases. (10th April 2015)

• Record Type: Journal Article
• Authors: Poláková, Monika; Stanton, Rhiannon; Wilson, Iain B.H.; Holková, Ivana; Šesták, Sergej; Machová, Eva; Jandová, Zuzana; Kóňa, Juraj
• Is Part Of: Carbohydrate research. Volume 406(2015)
• Page Start: 34
• Page End: 40
• Publication Date: 2015-04-10
• Subjects: Click reaction -- 1-(d-Mannopyranosyl)-1, 2, 3-triazole -- α-Mannosidase inhibitor -- Molecular docking -- Glycoside hydrolase; GMII Golgi α-mannosidase II -- hGMII human Golgi α-mannosidase II -- dGMII Drosophila melanogaster α-mannosidase II -- dGMIIb catalytic domain of Drosophila melanogaster Co(II)-activated Golgi α-mannosidase IIb, recombinant enzyme homolog of human Golgi α-mannosidase II -- LM lysosomal α-mannosidase -- hLM human lysosomal α-mannosidase -- bLM Bos taurus lysosomal α-mannosidase -- dLManII catalytic domain of Drosophila melanogaster lysosomal α-mannosidase II, recombinant enzyme homolog of human lysosomal α-mannosidase -- JBMan jack bean α-mannosidase (Canavalia ensiformis) -- AspMan Aspergillus saitoi α1, 2-mannosidase -- hERManI human endoplasmic reticulum α-mannosidase I; Carbohydrates -- Periodicals; Chemistry, Organic -- Periodicals; Biochemistry -- Periodicals; Carbohydrates -- Periodicals; Chimie organique -- Périodiques; Glucides -- Périodiques; Biochemistry; Carbohydrates; Chemistry, Organic; Periodicals; Electronic journals; 507.78
• DOI: 10.1016/j.carres.2015.01.004
• Languages: English
• ISSNs: 0008-6215

Abstract

Abstract: Three new triazole conjugates derived fromd -mannose were synthesized and assayed in in vitro assays to investigate their ability to inhibit α-mannosidase enzymes from the glycoside hydrolase (GH) families 38 and 47. The triazole conjugates were more selective for a GH47 α-mannosidase (Aspergillus saitoi α1, 2-mannosidase), showing inhibition at the micromolar level (IC50 values of 50–250 μM), and less potent towards GH38 mannosidases (IC50 values in the range of 0.5–6 mM towards jack bean α-mannosidase or Drosophila melanogaster lysosomal and Golgi α-mannosidases). The highest selectivity ratio [IC50 (GH38)/IC50 (GH47)] of 100 was exhibited by the phenyltriazole conjugate. To understand structure-activity properties of synthesized compounds, 3-D complexes of inhibitors with α-mannosidases were built using molecular docking calculations. Graphical abstract: Highlights: d -Mannosyl triazoles for inhibition of α-mannosidases from the GH families 38 and 47. Triazoles were more efficient inhibitors towards α-mannosidase from the GH family 47. A selectivity ratio [IC50 (GH38)/IC50 (GH47)] of 100 for the most selective triazole. 3-D complexes (inhibitor-enzyme) were built using molecular docking calculations.