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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 26, 2008
• 年：2008
• 卷：51
• 期：12
• 页码：3540 - 3554
• 全文大小：2656K
• 年卷期：v.51,no.12(June 26, 2008)
• ISSN：1520-4804

文摘

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.