Design and synthesis of semi-synthetic and partial analogs of oleanolic acid as potential complement inhibitors.

摘要

While complement activation protects the body from invading microorganisms, unwanted and excessive activation contributes to the pathogenesis of various inflammatory diseases as well as hyperacute rejection of xenotransplants. In an effort to develop clinically useful potential complement inhibitors, we used oleanolic acid as a drug design lead. Oleanolic acid is a triterpene natural product which inhibits the classical pathway of the complement system in vitro and complement-mediated inflammation in vivo.;To help delineate the structure-complement inhibitory relationship, we have synthesized a series of oleanolic acid semi-synthetic and partial analogs and tested for their complement inhibitory activity. All the synthesized analogs have also been examined for their cytotoxic properties. In view of the structural similarity of oleanolic acid to betulinic acid (an apoptosis inducing compound), the semi-synthetic derivatives have been tested for their ability to induce apoptosis.;In the semi-synthetic analog series, N-[3beta-hydroxyolean-12(13)-en-28-oyl]-5-aminopentanoic acid (41) and 3-O-diglycolyl-oleanolic acid (48) show potency superior to oleanolic acid. Both have also shown a moderate improvement in the in vitro therapeutic index (T.I.) and may serve as improved drug leads. 3beta-Acetyl oleanolic acid amide (35) and 3-oxoolean-12-en-28-oic acid (50) have cytotoxicity similar to betulinic: acid, but did not show complement inhibitory activity. Although most of the compounds with cytotoxic activity have shown apoptotic property, apoptosis was not consistently correlated with cytotoxicity. All the six final and one intermediate A/B-ring partial analogs have shown moderate complement inhibitory potency with T.I. of less than one. The flexible synthetic route developed for this series of partial analogs should allow easy access to various analogs for further structure-activity relationship studies.