New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-benzothiazolones

Here, we describe the synthesis, characterization, and biological activities of a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4). The cytotoxic activities of these compounds were tested in several cell lines (EA.hy926, A549, BEAS-2B, MDA-MB-231, HT-29, MCF-7, and MCF-10A), and the relations between structure and cytotoxicity are discussed. From the series, compound (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzothiazolone (26Z) exhibits the most potent cytotoxic activity (IC50 0.13 +/- 0.01 mu M) against EA.hy926 cells. 26Z not only inhibits vasculogenesis but also disrupts pre-existing vasculature. 26Z is a microtubule-modulating agent and inhibits a spectrum of angiogenic events in EA.hy926 cells by interfering with endothelial cell invasion, migration, and proliferation. 26Z also shows anti-proliferative activity in CA-4 resistant cells with the following IC50 values: HT-29 (0.008 +/- 0.001 mu M), MDA-MB-231 (1.35 +/- 0.42 mu M), and MCF-7 (2.42 +/- 0.48 mu M). Cell-cycle phase-specific experiments show that 26Z treatment results in G2/M arrest and mitotic spindle multipolarity, suggesting that drug-induced centrosome amplification could promote cell death. Some 26Z-treated adherent cells undergo aberrant cytokinesis, resulting in aneuploidy that perhaps contributes to drug-induced cell death. These data indicate that spindle multipolarity induction by 26Z has an exciting chemotherapeutic potential that merits further investigation.

Automated summary

In this study, a series of 26 new styryl-2(3H)-benzothiazolone analogs of combretastatin-A4 (CA-4) were synthesized, characterized, and tested for their biological activities. Compound 26Z showed the most potent cytotoxic activity against EA.hy926 cells and demonstrated anti-vasculogenic effects. Furthermore, 26Z exhibited anti-proliferative activity in CA-4 resistant cells and induced G2/M arrest and mitotic spindle multipolarity, suggesting its potential as a new chemotherapeutic agent with further investigation needed.