3-oxo-12-ursen-28-oic-acid and asiatic-acid

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.

Topics: Adenosine Monophosphate; Allosteric Site; Animals; Binding Sites; Crystallography, X-Ray; Glycogen Phosphorylase; Hypoglycemic Agents; Kinetics; Models, Molecular; Muscles; Oleanolic Acid; Pentacyclic Triterpenes; Protein Binding; Protein Conformation; Rabbits; Stereoisomerism; Structure-Activity Relationship; Triterpenes