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HERO ID
4239670
Reference Type
Journal Article
Title
A fluorine scan of a tubulin polymerization inhibitor isocombretastatin A-4: Design, synthesis, molecular modelling, and biological evaluation
Author(s)
Naret, T; Bignon, J; Bernadat, G; Benchekroun, M; Levaique, H; Lenoir, C; Dubois, J; Pruvost, A; Saller, F; Borgel, D; Manoury, B; Leblais, V; Darrigrand, R; Apcher, S; Brion, JD; Schmitt, E; Leroux, FR; Alami, M; Hamze, A
Year
2018
Is Peer Reviewed?
Yes
Journal
European Journal of Medicinal Chemistry
ISSN:
0223-5234
EISSN:
1768-3254
Volume
143
Page Numbers
473-490
Language
English
PMID
29202409
DOI
10.1016/j.ejmech.2017.11.055
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 IC50values 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.
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