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


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.

SUBMITTER: Atanasov G 

PROVIDER: S-EPMC8703450 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Atanasov Gjorgji G   Rusew Rusi I RI   Gelev Vladimir M VM   Chanev Christo D CD   Nikolova Rosica R   Shivachev Boris L BL   Petrov Ognyan I OI   Apostolova Margarita D MD  

Pharmaceuticals (Basel, Switzerland) 20211220 12


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 (<i>Z</i>)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3<i>H</i>)-benzothiazolone (<b>26Z</b>) exhibits  ...[more]

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