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Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure−Activity Relationships, and X-ray Crystallographic Studies

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journal contribution
posted on 26.06.2008, 00:00 by Xiaoan Wen, Hongbin Sun, Jun Liu, Keguang Cheng, Pu Zhang, Liying Zhang, Jia Hao, Luyong Zhang, Peizhou Ni, Spyros E. Zographos, Demetres D. Leonidas, Kyra-Melinda Alexacou, Thanasis Gimisis, Joseph M. Hayes, Nikos G. Oikonomakos
Twenty-five naturally occurring pentacyclic triterpenes, 15 of which were synthesized in this study, were biologically evaluated as inhibitors of rabbit muscle glycogen phosphorylase a (GPa). From SAR studies, the presence of a sugar moiety in triterpene saponins resulted in a markedly decreased activity (7, 1820) or no activity (21, 22). These saponins, however, might find their value as potential natural prodrugs which are much more water-soluble than their corresponding aglycones. To elucidate the mechanism of GP inhibition, we have determined the crystal structures of the GPb−asiatic acid and GPb−maslinic acid complexes. The X-ray analysis indicates that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Pentacyclic triterpenes represent a promising class of multiple-target antidiabetic agents that exert hypoglycemic effects, at least in part, through GP inhibition.