ABSTRACT
We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via "abnormal Beckmann" rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Drug Design , Inflammation/drug therapy , Oleanolic Acid/analogs & derivatives , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Female , Inflammation/metabolism , Mice , Molecular Conformation , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , RAW 264.7 CellsABSTRACT
An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester) from commercially available ursolic acid, which features an oxidative ozonolysis-mediated C-ring enone formation, and provides the first access to ursolic acid-derived cyano enone analogues with C-ring activation. These new ursolic acid analogues show potent biological activities, with potency of approximately five-fold less than the corresponding oleanolic acid derivatives.
