Synthesis of a C-glucosylated cyclopropylamide and evaluation as a glycogen phosphorylase inhibitor.
The synthesis of carbohydrate-based glycogen phosphorylase inhibitors is attractive for potential applications in the treatment of type 2 diabetes. A titanium-mediated synthesis led to a benzoylated C-glucosylated cyclopropylamine intermediate, which underwent a benzoyl migration to afford the corresponding 2-hydroxy-C-glycoside. X-ray crystallographic studies revealed a unit cell composed of four molecules as pairs of dimers connected through two hydrogen bonds. The deprotection of the benzoate esters under Zemplén conditions afforded a glycogen phosphorylase inhibitor candidate displaying weak inhibition toward glycogen phosphorylase (16% at 2.5mM).
Bertus
Philippe
P
CNRS UMR 6011, Unité de Chimie Organique Moléculaire et Macromoléculaire (UCO2M), Université du Maine, Avenue O. Messiaen, F-72085 Le Mans Cedex 9, France.
Szymoniak
Jan
J
Jeanneau
Erwann
E
Docsa
Tibor
T
Gergely
Pál
P
Praly
Jean-Pierre
JP
Vidal
Sébastien
S
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004353:Drug Evaluation, Preclinical; D005960:Glucosides / Q000138:chemical synthesis / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism*; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors / Q000378:metabolism; D024982:Glycogen Phosphorylase, Muscle Form / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006031:Glycosylation; D011817:Rabbits
D001549:Benzamides; D005960:Glucosides; D006003:Glycogen; D025001:Glycogen Phosphorylase, Liver Form; D024982:Glycogen Phosphorylase, Muscle Form