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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.

The synthesis and biological evaluation of corosolic acid derivatives and related compounds as inhibitors of rabbit muscle glycogen phosphorylase a is described. Within this series of compounds, 8 (IC(50)=7.31 microM), 12d (IC(50)=3.26 microM), and 12e (IC(50)=5.1 microM) exhibited more potent activities than the parent compound 1 (IC(50)=20 microM). SAR of these compounds is also discussed.

The semi-synthesis, in vitro and in vivo biological evaluation of corosolic acid (1) and maslinic acid (2) are described. Compounds 1 and 2 represent a new class of inhibitors of glycogen phosphorylases. Both 1 and 2 inhibit the increase of fasted plasma glucose of diabetic mice induced by adrenaline. It is therefore proposed that naturally occurring pentacyclic triterpenes 1 and 2 might reduce blood glucose, at least in part, through inhibiting hepatic glycogen degradation.

Antidiabetic agents simultaneously inhibiting hepatic glucose production and stimulating hepatic glucose consumption could apply a better control over hyperglycemia. A series of oleanolic acid derivatives with bulky substituents at C-3 position were designed and synthesized in order to search for this kind of agents. All of the compounds were evaluated biologically in vitro using glycogen phosphorylase and HepG2 cells. The results indicated that several derivatives exhibited moderate-to-good inhibitory activities against glycogen phosphorylase. Compound 8g showed the best inhibition with an IC50 value of 5.4 μ m. Moreover, most of the derivatives were found to increase the glucose consumption in HepG2 cells in a dose-dependent manner. The possible binding mode of compound 8g with glycogen phosphorylase was also explored by docking study. 8g was found to have hydrogen bonding interactions with Arg193, Arg310, and Arg60 of the allosteric site. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of a series of maslinic acid derivatives is described and their effect on rabbit muscle glycogen phosphorylase a evaluated. Within this series of compounds, 15 (IC50 =7μM) is the most potent GPa inhibitor. SAR of the maslinic acid derivatives are discussed. [Copyright &y& Elsevier]

Abstract: Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure–activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1μM. [Copyright &y& Elsevier]