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|Title:||Naturally occurring pentacyclic triterpenes as inhibitors of glycogen phosphorylase: Synthesis, structure-activity relationships, and X-ray crystallographic studies|
Zographos, Spyros E.
Leonidas, Demetres D.
Hayes, Joseph M.
Oikonomakos, Nikos G.
|Type:||Journal Article (Scientific Journal article)|
|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.|
|Publisher:||American Chemical Society|
|Journal Title:||Journal of Medicinal Chemistry|
|Subject Category:||Science::Chemistry (General)|
Medicine::Pharmacy and materia medica
|Other Identifiers:||DOI: http://dx.doi.org/10.1021/jm8000949|
|Journal web Location :||http://pubs.acs.org/jmc|
|Rights holder:||© AMER CHEMICAL SOC|