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The combretastatins (<i>cis</i>-stilbenoid molecules) have received significant interest because of their simple chemical structures, excellent antiproliferative activity, and novel anti-tubulin molecular mechanism of action. Significant efforts have been carried out aiming at stabilizing the active <i>cis</i>-isomers. A new series of <i>cis</i>-vinylamide derivatives containing trimethoxyphenyl moiety were synthesized and characterized. Their anticancer activities were evaluated in vitro against MCF-7 breast cancer cell line. Compounds <b>2f</b>, <b>3</b>, and <b>5</b> displayed potent cytotoxic activity against the breast cancer cell line compared with CA-4 as the reference compound. The microtubule polymerization assay and flow cytometry analysis confirmed that the cytotoxic activity of compound <b>3</b> was related to inhibitory activity against tubulin polymerization. Compound <b>3</b> showed pro-apoptotic activity by inducting a significant increase in the percentage of pre-G1 phase in DNA flow cytometry compared to untreated control. The pro-apoptotic activity of compound <b>3</b> was inferred by a significant increase in the percentage of fluorescent annexin V/PI positive apoptotic cells. It also increased the level of caspase 3 compared to the untreated control.