Synthesis And Antitumor Activity Of Combretastatin A - 4 Analogues Of 2,3 - Diarylthiophenes

Combretastatin A-4 (CA-4), naturally occurring stilbenes, was isolated from Combretum caffrum by Pettit group. This substance strongly inhibited the polymerization of tubulin by binding to the chochicine site and showed most potent cytotoxicity against a variety of human cancer cell lines including multiple drug-resistant cancer cell lines.From the previous comparative studies of the combretastatins, it appears that the cis orientation of the two aromatic rings plays an important key role in cytotoxicity. However, during storage and administration cis-combretastatin analogues tend to isomerize to trans-forms which show a dramatic decrease in their inhibitory effects on cancer cell growth and tubulin polymerization.In our efforts to discover active antimitotic agents, we utilized thiophene ring to mimic the cis double bond in CA-4 to avoid the stability problem. In this study, two different 1,2-diarylethanone were respectively prepared from the starting 3,4,5- trimethoxybenzaldehyde by two simple "one pot" reactions, which were then converted to the corresponding ethyl 4,5-diarylthiophene -2- carboxylate derivatives by Vilsmeier-Haack reaction and cyclization reaction. Treatment of the ethyl 4,5-diarylthiophene -2- carboxylate with NaOH under reflux resulted in the corresponding 4,5-diarylthiophene -2- carboxylic acid derivatives which were then reacted with Cu2O to yield desired 2,3-diarylthiophene derivatives. The structures of these compounds were confirmed by detailed NMR/MS analysis.Cytotoxic activity of these compounds was evaluated against human cancer cell lines including human colon carcinoma(LoVo), human adenocarcinoma of lung(A549), human T Lymphocytic leukemia(Jurkat T). The result showed that A-5-3, B-5-2, B-5-4exerted high cytotoxicities against all of the tested tumor cell lines.