A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation

Naret, Timothée, Bignon, Jérôme, Bernadat, Guillaume, Benchekroun, Mohamed, Levaique, Helene, Lenoir, Christine, Dubois, Joelle, Pruvost, Alain, Saller, François, Borgel, Delphine, Manoury, Boris, Leblais, Veronique, Darrigrand, Romain, Apcher, Sébastien, Brion, Jean-Daniel, Schmitt, Etienne, Leroux, Frédéric R, Alami, Mouad and Hamze, Abdallah (2018) A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation. European Journal of Medicinal Chemistry, 143. pp. 473-490. ISSN 0223-5234

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Abstract

A novel series of tubulin polymerization inhibitors, based on fluorinated derivatives of isocombretastatin A-4 was synthesized with the goal of evaluating the effect of these compounds on the proliferative activity. The introduction of fluorine atom was performed on the phenyl ring or at the linker between the two aromatic rings. The modification of isoCA-4 by introduction of difluoromethoxy group at the para-position (3i) and substitution of the two protons of the linker by two fluorine atoms (3m), produced the most active compounds in the series, with IC50 values of 0.15–2.2 nM (3i) and 0.1–2 nM (3m) respectively, against a panel of six cancer cell lines. Compounds 3i and 3m had greater antiproliferative activity in comparison with references CA-4 or isoCA-4, the presence of fluorine group leads to a significant enhancement of the antiproliferative activity. Molecular docking studies indicated that compounds 3i and 3m occupy the colchicine binding site of tubulin. Evaluation of cytotoxicity in Human noncancer cells indicated that the compounds 3i and 3m were practically ineffective in quiescent peripheral blood lymphocytes, and may have a selective antiproliferative activity against cancer cells. Analyses of cell cycle distribution, and morphological microtubules organization showed that compound 3m induced G2/M phase arrest and, dramatically disrupted the microtubule network.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Research Centres and Groups: Sussex Drug Discovery Centre
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
R Medicine > RS Pharmacy and materia medica > RS0153 Materia medica > RS0400 Pharmaceutical chemistry
Depositing User: Mohamed Benchekroun
Date Deposited: 31 Jan 2018 15:53
Last Modified: 31 Jan 2018 15:53
URI: http://sro.sussex.ac.uk/id/eprint/73257
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