'Click chemistry' synthesis of 1-(α-D-mannopyranosyl)-1,2,3-triazoles for inhibition of α-mannosidases

Carbohydr Res. 2015 Apr 10:406:34-40. doi: 10.1016/j.carres.2015.01.004. Epub 2015 Jan 19.

Abstract

Three new triazole conjugates derived from d-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.

Keywords: 1-(d-Mannopyranosyl)-1,2,3-triazole; Click reaction; Glycoside hydrolase; Molecular docking; α-Mannosidase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Click Chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Humans
  • Models, Molecular
  • Protein Binding
  • Triazoles / chemical synthesis*
  • alpha-Mannosidase / antagonists & inhibitors
  • alpha-Mannosidase / chemistry*

Substances

  • Enzyme Inhibitors
  • Triazoles
  • alpha-Mannosidase