Biological evaluation of 3′-O-alkylated analogs of salacinol, the role of hydrophobic alkyl group at 3′ position in the side chain on the α-glucosidase inhibitory activity

Four analogs with 3′-O-alkyl groups (9a: CH3, 9b: C2H5, 9c: C13H27 or 9d: CH2Ph) instead of the 3′-O-sulfate anion in salacinol (1), a naturally occurring potent α-glucosidase inhibitor, were synthesized by the coupling reaction of 1,4-dideoxy-1,4-epithio-d-arabinitols (18a and 18b) with appropriate epoxides (10a–10d). These analogs showed equal or considerably higher inhibitory activity against rat small intestinal α-glucosidases than the original sulfate (1), and one of them (9d) was found more potent than currently used α-glucosidase inhibitors as antidiabetics. Thus, introduction of a hydrophobic moiety at the C3′ position of this new class of inhibitor was found beneficial for onset of stronger inhibition against these enzymes.

Graphical abstractFour analogs (9) in which the 3′-O-sulfate anion of salacinol (1), a naturally occurring potent α-glucosidase inhibitor, was replaced by O-alkyl groups (a: OCH3, b: OC2H5, c: OC13H27 or d: OCH2Ph) were synthesized, and their α-glucosidase inhibitory activities were evaluated. All the analogues were found more potent than 1, and one of them (9d) showed excellent inhibitory activity which surpassed those of the currently used antidiabetics, acarbose and voglibose, against rat small intestinal maltase. Thus, introduction of hydrophobic moieties to C3′ position in this class of molecules was found beneficial for improvement of the inhibitory activity.Figure optionsDownload full-size imageDownload as PowerPoint slide