Design, Synthesis, and Investigation of Cytotoxic Activity of <i>cis</i>-Vinylamide-Linked Combretastatin Analogues as Potential Anticancer Agents

Abstract

The combretastatins (cis-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 cis-isomers. A new series of cis-vinylamide derivatives containing trimethoxyphenyl moiety were synthesized and characterized. Their anticancer activities were evaluated in vitro against MCF-7 breast cancer cell line. Compounds 2f, 3, and 5 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 3 was related to inhibitory activity against tubulin polymerization. Compound 3 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 3 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.

Keywords

• CA-4
• <i>cis</i>-vinylamide
• cytotoxicity
• microtubule
• cell cycle analysis
• annexin V