Abstract
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 µM) 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 µM), MDA-MB-231 (1.35 ± 0.42 µM), and MCF-7 (2.42 ± 0.48 µM). 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.
Highlights
Introduction published maps and institutional affilMicrotubules are intracellular polymers comprised of α,β-tubulin heterodimers
The synthesis of the target compounds from substituted methoxybenzaldehydes 5–8 and the phosphonium salts 11–13 (Path A), or 3-methyl-2(3H)-benzothiazolone-6-carbaldehyde or 3-methyl-2(3H)-benzothiazolone-7-carbaldehyde 9–10 and the phosphonium salt 14 (Path B), is shown in Scheme 1
5-methyl-2(3H)-benzothiazolone (29), we focused on regioselective method for obtaining 5-methyl-2(3H)-benzothiazolone (29), we focused on the oxidation of 2-mercaptobenzothiazoles
Summary
Microtubules are intracellular polymers comprised of α,β-tubulin heterodimers. They have essential cellular functions such as cell shape maintenance, organelle distribution, cell motility, and chromosome segregation [1]. Compounds that disrupt microtubule polymerization/depolymerization dynamics have been extensively studied as anticancer agents [2,3,4]. Such compounds include vinblastine, vincristine, and vinorelbine, which bind to tubulin’s vinca domain, while docetaxel and paclitaxel bind to the taxane-site. Isolated from the bark of the South African willow tree Combretum caffrum [6], CA-4 is one of the most potent inhibitors of tubulin polymerization, which interferes with microtubule dynamics and perturbs the mitotic cycle [7,8]. CA-4 causes disruption and collapse of tumor blood vessels and subsequent necrotic cell death of tumor iations
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