Flexible synthesis and biological activity of uronic acid-type gem-diamine 1-N-iminosugars: a new family of glycosidase inhibitors.
An efficient and flexible synthetic route to four gem-diamine 1-N-iminosugars of uronic acid-type (D-glucuronic, D-mannuronic, L-iduronic, and L-guluronic acid), a new family of glycosidase inhibitor, from l-galactono-1,4-lactone have been developed in an enantiodivergent fashion through a sequence involving as the key steps (a) the formation of gem-diamine 1-N-iminopyranose ring by the Mitsunobu reaction of an aminal and (b) the introduction of a carboxylic acid group by the Wittig reaction of a ketone, hydroboration and oxidation, and the Sharpless oxidation. D-Glucuronic and D-mannuronic acid-type 1-N-iminosugars, (3S,4R,5R, 6R)- and (3S,4R,5R,6S)-4, 5-dihydroxy-6-trifluoroacetamido-3-piperidinecarboxylic acid, were proven to be potent inhibitors for beta-D-glucuronidase (IC(50) 6.5 x 10(-)(8)M) and to affect human heparanase (endo-beta-glucuronidase).
Nishimura
Y
Y
Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
Shitara
E
E
Adachi
H
H
Toyoshima
M
M
Nakajima
M
M
Okami
Y
Y
Takeuchi
T
T
D000818:Animals; D002236:Carbohydrate Conformation; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D007097:Imines / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D014574:Uronic Acids / Q000737:chemistry*
D002241:Carbohydrates; D004791:Enzyme Inhibitors; D007097:Imines; D014574:Uronic Acids; D006026:Glycoside Hydrolases