Design and synthesis of aminostilbene-arylpropenones as tubulin polymerization inhibitors.

Abstract

A series of aminostilbene-arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50 % growth inhibition (GI50) values in the range from < 0.01 to 19.9 μM. One of the compounds showed a broad spectrum of antiproliferative efficacy on most of the cell lines, with a GI50 value of < 0.01 μM. All of the synthesized compounds displayed cytotoxicity against A549 (non-small-cell lung cancer), HeLa (cervical carcinoma), MCF-7 (breast cancer), and HCT116 (colon carcinoma) with 50 % inhibitory concentration (IC50) values ranging from 0.011 to 8.56 μM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79 μM. Moreover, dot-blot analysis of cyclin B1 demonstrated that some of the congeners strongly induced cyclin B1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.