Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that cyclooxygenase-1 (COX-1) plays an important role in inflammation and carcinogenesis. In order to find more selective COX-I inhibitors a series of novel curcumin derivatives was synthesized and evaluated for their ability to inhibit this enzyme using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. All curcumin analogues showed a higher rate of COX-I inhibition. The most potent curcumin compounds were (1E,6E)-1,7-di-(2,3,4-trimethoxyphenyl)-1,6-heptadien-3,5-dione (4) (COX-1: IC50=0.06 mu m, COX-2: IC50 > 100 mu m, selectivity index > 1666) and (1E,6E)methyl 4-[7-(4-methoxycarbonyl)phenyl]-3,5-dioxo-1,6-heptadienyl]benzoate (6) (COX-1: IC50=0.05 mu m, COX-2: IC50 > 100 mu m, selectivity index > 2000). Curcumin analogues therefore represent a novel class of highly selective COX-1 inhibitors and promising candidates for in vivo studies.