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

journal contribution
posted on 2023-06-09, 11:51 authored by Timothée Naret, Jérôme Bignon, Guillaume Bernadat, Mohamed Benchekroun, Helene Levaique, Christine Lenoir, Joelle Dubois, Alain Pruvost, François Saller, Delphine Borgel, Boris Manoury, Veronique Leblais, Romain Darrigrand, Sébastien Apcher, Jean-Daniel Brion, Etienne Schmitt, Frédéric R Leroux, Mouad Alami, Abdallah Hamze
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.

History

Publication status

  • Published

Journal

European Journal of Medicinal Chemistry

ISSN

0223-5234

Publisher

Elsevier

Volume

143

Page range

473-490

Department affiliated with

  • Chemistry Publications

Research groups affiliated with

  • Sussex Drug Discovery Centre Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2018-01-31

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