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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Wen X,Sun H,Liu J,Cheng K,Zhang P,Zhang L,Hao J,Zhang L,Ni P,Zographos SE,Leonidas DD,Alexacou KM,Gimisis T,Hayes JM,Oikonomakos NG

doi

10.1021/jm8000949

subject

Has Abstract

pub_date

2008-06-26 00:00:00

pages

3540-54

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

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