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Issue 3, 2013
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Synthesis, biological evaluation, and structure–activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors

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Abstract

The synthesis and structure–activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI50 = 8–80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC50 values of 2 and 3 μM, respectively, and induced cell cycle arrest in the G2/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.

Graphical abstract: Synthesis, biological evaluation, and structure–activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors

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Publication details

The article was received on 02 Jul 2012, accepted on 19 Sep 2012 and first published on 19 Sep 2012


Article type: Paper
DOI: 10.1039/C2OB26253C
Citation: Org. Biomol. Chem., 2013,11, 430-442
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    Synthesis, biological evaluation, and structure–activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors

    J. Aziz, E. Brachet, A. Hamze, J. Peyrat, G. Bernadat, E. Morvan, J. Bignon, J. Wdzieczak-Bakala, D. Desravines, J. Dubois, M. Tueni, A. Yassine, J. Brion and M. Alami, Org. Biomol. Chem., 2013, 11, 430
    DOI: 10.1039/C2OB26253C

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