Synthesis and biological evaluation of potent glycosidase inhibitors: N-phenyl cyclic isourea derivatives of 5-amino- and 5-amino-C-(hydroxymethyl)-1,2,3,4-cyclopentanetetraols.
Twenty-four stereoisomers of 5-amino- and 5-amino-C-(hydroxymethyl)-1,2,3,4-cyclopentanetetraols and twenty-six of the corresponding N-phenyl cyclic isourea derivatives were assayed for inhibitory activity against six glycosidases. Among them, as has been expected for structure mimics of putative transition state glucopyranosyl cation for glycoside hydrolysis, 1L-(1,2,4,5/3)-5-amino-1-C-(hydroxymethyl)-1,2,3,4-cyclopentanetetrao l L-4 and its N-phenyl cyclic isourea derivative S-19 were shown to have strong inhibitory activity, IC50 4 x 10(-7) and 7.6 x 10(-9) M, respectively, against baker's yeast alpha-glucosidase. It has been analogously explained that compounds R,S-22 and R,S-26 possessed high inhibitory potency against Escherichia coli and bovine liver beta-galactosidases, respectively.
Uchida
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C
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
Kimura
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H
Ogawa
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D000818:Animals; D002417:Cattle; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D008361:Mannosidases / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014198:Trehalase / Q000037:antagonists & inhibitors; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors; D043323:alpha-Mannosidase; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors; D001617:beta-Glucosidase / Q000037:antagonists & inhibitors
D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D006026:Glycoside Hydrolases; D008361:Mannosidases; D001617:beta-Glucosidase; D000519:alpha-Galactosidase; D001616:beta-Galactosidase; D043323:alpha-Mannosidase; D014198:Trehalase