Chemmedchem 2011-12-09

B-ring-modified isocombretastatin A-4 analogues endowed with interesting anticancer activities.

Abdallah Hamze, Evelia Rasolofonjatovo, Olivier Provot, Céline Mousset, Damien Veau, Jordi Rodrigo, Jérôme Bignon, Jian-Miao Liu, Joanna Wdzieczak-Bakala, Sylviane Thoret, Joëlle Dubois, Jean-Daniel Brion, Mouad Alami

Index: ChemMedChem 12th ed., 6 , 2179-2191, (2011)

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Abstract

A novel class of isocombretastatin A-4 (isoCA-4) analogues with modifications at the 3'-position of the B-ring by replacement with C-linked substituents was studied. Exploration of the structure-activity relationships of theses analogues led to the identification of several compounds that exhibit excellent antiproliferative activities in the nanomolar concentration range against H1299, MDA-MB231, HCT116, and K562 cancer cell lines; they also inhibit tubulin polymerization with potency similar to that of isoCA-4. 1,1-Diarylethylenes 8 and 17, respectively with (E)-propen-3-ol and propyn-3-ol substituents at the 3'-position of the B-ring, proved to be the most active in this series. Both compounds led to the arrest of various cancer cell lines at the G(2) /M phase of the cell cycle and strongly induced apoptosis. Docking of compounds 8 and 17 in the colchicine binding site indicated that their C3' substituents guide the positioning of the B-ring in a manner different from that observed for isoCA-4.Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.