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

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.

Figure 1

(A) A superposition of the compounds 6 (with carbons in green), 7 (in yellow) and 8 (in magenta) docked in the active site of hERManI (PDB ID: 1FO3); (B) Selected interactions between the inhibitor 6 (in red) and hERManI.

Figure 2

A superposition of the compound 7 with an analogous mannoside 9 with the triazole group substituted by the sulfone group in the active site of dGMII (PDB ID: 3BLB). For a comparison, interactions of triazole and sulfone group with active-site amino acid residues of dGMII (Asp341, Tyr269 and Arg228) are visualized.

Figure 3

The best five docking poses for the triazole 7 found for dGMII and bLM. In both cases the benzyl moiety of the inhibitor was found in two binding sites (B1 and B2). A binding site (B3) which may be responsible for a selective binding of the inhibitor was empty. This may explain the lack of selectivity observed for the triazole mannosides.

Scheme 1

Reagents and conditions. (a) 2a, 2b or 2c, CuSO₄, sodium ascorbate, DMF:H₂O 3:1, 3 h, rt, 86-91%; (b) K₂CO₃, MeOH, 30 min, rt, 87-93%.