Combretastatins-A4 (CA-4) is a natural product with extraordinary anticancer activity, which was isolated from the South African Tree-Combretum caffrum. However, the cis-isomer exhibits strong antitubulin activity only, but the cis-isomer tends to isomerize the inactive trans-isomer. In this paper, an additional pyrrolidone ring system was used to replace the cis double bond to arrest the cis-conformation. Thus, four new compounds of 3,4-diaryl pyrrolediones and 3,4-diaryl pyrrolones as CA-4 analogues were synthesized from the starting materials 3,4-dimethoxyacetophenone or 3-fluoro-4-methoxy acetophenone, via a four steps reaction, α-bromination, improved Gabriel reaction, condensation with 3,4,5-trimethoxyphenylacetic acid and intramolecular cyclization under air or nitrogen. The structures of these new compounds were confirmed by ¹H NMR, ¹³C NMR, ESI-MS and elemental analysis. The in vitro antitumor activities of CA-4 analogues against HL-60, SMMC-7721 and A549 human gastric cancer cell lines were tested using colorimetric MTT assay. The preliminary result indicates that 3-(3-fluoro-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)pyrrole-2,5-dione (1b) shows significant antitumor activity (0.03～0.05 μmol·L^-1), which is closely to the natural CA-4.

Key words: combretastatin A-4 analogues, synthesis, antitumor activity, 3,4-diaryl pyrroledione, 3,4-diaryl pyrrolone