Design and synthesis of 5a-carbaglycopyranosylamime glycosidase inhibitors.
5a-Carba-alpha-D-glucopyranosylamine, validamine, and analogous compounds valienamine and valiolamine, have proved to be important lead compounds for development of clinically useful medicines, including the very strong alpha-glucosidase inhibitor, voglibose, N-(1,3-dihydroxyprop-2-yl)valiolamine, now used widely as a clinically important antidiabetic agent. In this review, we describe recent advances in development of glycosidase inhibitors on the basis of the ground-state mimics of the postulated glycopyranosyl cation, considered to be formed during hydrolysis of glycopyranosides, and introduce a new type of highly potent alpha-fucosidase inhibitor, 5a-carba-alpha-L-fucopyranosylamine, alpha-fuco validamine. Interestingly, the corresponding beta-anomer, and in particular its D-enantiomer, has been shown to possess very strong cross-inhibitory activity toward beta-galactosidase and beta-glucosidase. Structure and inhibitory activity relationships concerning these alpha,beta-fuco derivatives, as well as parent alpha,beta-galacto validamines are discussed here with reference to our results.
Ogawa
Seiichiro
S
Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama, Japan. sogawa379@ybb.ne.jp
Kanto
Miki
M
D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005643:Fucose / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006595:Hexosamines / Q000138:chemical synthesis*; D007294:Inositol / Q000031:analogs & derivatives / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors
C461193:5a-carbafucopyranosylamine; D004791:Enzyme Inhibitors; D006595:Hexosamines; D005643:Fucose; C042908:validamine; D007294:Inositol; D006026:Glycoside Hydrolases; D005644:alpha-L-Fucosidase