Synthesis and antitumor activities of novel CDDO-Me analogues

The novel oleanolic acid derivatives 2a-2e were synthesized by introducing an α,β-unsaturated ketone moiety to C-ring of oleanolic acid (OA) via a nine-step reaction sequence, yielding an active CDDO-Me analogue (1), followed by coupling of C3-OH of 1 with various aliphatic and aromatic carboxylic acids, respectively. Derivatives 3a-3e were synthesized by substituting C-1 of compounds 2a-2e with bromine. The target compounds were characterized by IR, MS and ¹H NMR spectra. All the target compounds showed strong inhibitory effects against two tumor cell lines (HepG2 and A549) to a varying extent. The anti-proliferative activities of active compounds 3b and 3c (IC₅₀ =6.13 ±1.16 μmol/L and IC₅₀ =5.49 ± 1.03 μmol/L, respectively) against HepG2 and A549 were more potent than compound 1 and comparable to the positive control CDDO-Me. In addition, all the target compounds displayed much weaker anti-proliferative activity against the two tumor cell lines than that against normal BEAS-2B cells. Compound 3c showed ten-fold selective inhibition against HepG2 relative to BEAS-2B cells, and is thus worthy of further study.