Naturally occurring pentacyclic triterpenes as inhibitors of glycogen phosphorylase: synthesis, structure-activity relationships, and X-ray crystallographic studies.

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

Index: J. Med. Chem. 51 , 3540-54, (2008)

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Abstract

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, 18- 20) 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.