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-1 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-1 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: IC(50) = 0.06 microM, COX-2: IC(50) > 100 microM, selectivity index>1666) and (1E,6E)-methyl 4-[7-(4-methoxycarbonyl)phenyl]-3,5-dioxo-1,6-heptadienyl]benzoate (6) (COX-1: IC(50) = 0.05 microM, COX-2: IC(50) > 100 microM, selectivity index > 2000). Curcumin analogues therefore represent a novel class of highly selective COX-1 inhibitors and promising candidates for in vivo studies.
Handler
Norbert
N
Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
Jaeger
Walter
W
Puschacher
Helmut
H
Leisser
Klaus
K
Erker
Thomas
T
D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization
D016861:Cyclooxygenase Inhibitors; D051545:Cyclooxygenase 1; D003474:Curcumin