Design, synthesis, and biological evaluation of novel combretastatin A-4 thio derivatives as microtubule targeting agents

European Journal of Medicinal Chemistry
Tomasz StefańskiStanisław Sobiak

Abstract

A series of novel combretastatin A-4 (CA-4) thio derivatives containing different molecular cores, namely α-phenylcinnamic acids (core 1), (Z)-stilbenes (core 2), 4,5-disubstituted oxazoles (core 3), and 4,5-disubstituted N-methylimidazoles (core 4), as cis-restricted analogues were designed and synthesized. They were selected with the use of a parallel virtual screening protocol including the generation of a virtual combinatorial library based on an elaborated synthesis protocol of CA-4 analogues. The selected compounds were evaluated for antiproliferative activity against a panel of six human cancer cell lines (A431, HeLa, MCF7, MDA-MB-231, A549 and SKOV) and two human non-cancer cell lines (HaCaT and CCD39Lu). Moreover, the effect of the test compounds on the inhibition of tubulin polymerization in vitro was estimated. In the series studied here, oxazole-bridged analogues exhibited the most potent antiproliferative activity. Compounds 23a, 23e, and 23i efficiently inhibited tubulin polymerization with IC50values of 0.86, 1.05, and 0.85 μM, respectively. Thio derivative 23i, when compared to its oxygen analogue 23j, showed a 5-fold higher inhibitory impact on tubulin polymerization. Compounds 23e and 23i, which showed both be...Continue Reading

Citations

Jul 31, 2020·Biomolecules·Paulina PecynaMalgorzata Kucinska
Mar 17, 2019·International Journal of Molecular Sciences·Natalia Piekuś-SłomkaStanisław Sobiak
Nov 15, 2018·International Journal of Molecular Sciences·Anna Lichota, Krzysztof Gwozdzinski
Mar 7, 2020·Acta Crystallographica. Section C, Structural Chemistry·Kalina MambourgJohan Wouters
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Jun 17, 2020·Current Topics in Medicinal Chemistry·Yingge WangYongtao Duan
Mar 7, 2021·International Journal of Molecular Sciences·Myriam GonzálezRafael Peláez
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anita M GrześkiewiczMaciej Kubicki
Nov 22, 2021·Experimental Neurology·Olga TarasiukCristina Meregalli

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