Simple Synthesis of Sulfonyl Amidine-Containing Glucosidase Inhibitors by a Chemoselective Coupling Reaction Between D-Gluconothiolactam and Sulfonyl Azides
Muhammad Aswad
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan and Faculty of Pharmacy, Hasanuddin University, Makassar, South Sulawesi 90245, Indonesia
Junya Chiba *
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Takenori Tomohiro
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Yasumaru Hatanaka
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
*Author to whom correspondence should be addressed.
Abstract
In this report, we describe a simple synthesis of gluconoamidinylsulfones as a new class of potential inhibitors toward glycan processing enzymes. Gluconoamidinylsulfones have a glucose-based sulfonyl amidine skeleton, thus would form a distorted half-chair conformation with positive charge, which is analogous to transition state in the enzymatic process. A chemoselective coupling reaction between thioamide and sulfonyl azide enabled one-step synthesis of the iminosugar derivatives from commercially available D-gluconothiolactam in a protection-free manner. The phenyl-substituted gluconoamidinylsulfone displayed high inhibitory ability toward a- and b-glucosidases with Ki values of 13.9 and 8.2 mM, respectively, resulting that gluconoamidinylsulfones would be expected to entry in a new class of promising potential inhibitors toward various glycan-processing enzymes.
Keywords: Inhibitor, glycosidase, iminosugar, coupling reaction, one-step synthesis, thioamide, sulfonyl azide, gluconoamidinylsulfone