Chemoenzymatic and Protecting-Group-Free Synthesis of 1,4-Substituted 1,2,3-Triazole-α-d-glucosides with Potent Inhibitory Activity toward Lysosomal α-Glucosidase

Abstract

α-Glucosyl triazoles have rarely been tested as α-glucosidase inhibitors, partly due to inefficient synthesis of their precursor α-d-glucosylazide (αGA1). Glycosynthase enzymes, made by nucleophile mutations of retaining β-glucosidases, produce αGA1 in chemical rescue experiments. Thermoanaerobacterium xylanolyticus glucosyl hydrolase 116 β-glucosidase (TxGH116) E441G nucleophile mutant catalyzed synthesis of αGA1 from sodium azide and pNP-β-d-glucoside (pNPGlc) or cellobiose in aqueous medium at 45 °C. The pNPGlc and azide reaction product was purified by Sephadex LH-20 column chromatography to yield 280 mg of pure αGA1 (68% yield). αGA1 was successfully conjugated with alkynes attached to different functional groups, including aryl, ether, amine, amide, ester, alcohol, and flavone via copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reactions. These reactions afforded the 1,4-substituted 1,2,3-triazole-α-d-glucoside derivatives AGT2-14 without protection and deprotection. Several of these glucosyl triazoles exhibited strong inhibition of human lysosomal α-glucosidase, with IC50 values for AGT4 and AGT14 more than 60-fold lower than that of the commercial α-glucosidase inhibitor acarbose.

1,2,3-Triazole Containing Hybrids as Potential Pharmacological Agents: A Review

“…Gorantla et al [135] synthesized the 1,2,3-triazole-α-Dglucoside derivatives. Among the synthesized derivatives, several compounds exhibited strong inhibition of human lysosomal α-glucosidase activity.…”

Recent Advances in Bioactive Flavonoid Hybrids Linked by 1,2,3-Triazole Ring Obtained by Click Chemistry

“…The 1,2,3-triazole-linked flavone-α- d -glucoside 83 ( Figure 29 ) was obtained with 47% yield by Click Chemistry reaction between O -propargylated chrysin and α- d -glucosylazide in the presence of CuI, DIPEA and TBTA in acetonitrile, at room temperature [ 125 ]. This compound provided a strong inhibition of α-glucosidase (IC 50 = 17 µM), 60-fold higher than the positive control acarbose (IC 50 =1100 µM).…”