Allocolchicinoids bearing a Michael acceptor fragment for possible irreversible binding of tubulin

Ekaterina S. Sazanova; Iuliia A. Gracheva; Diane Allegro; Pascale Barbier; Sébastien Combes; Elena V. Svirshchevskaya; Alexey Yu Fedorov

doi:10.1039/D0MD00060D

Allocolchicinoids bearing a Michael acceptor fragment for possible irreversible binding of tubulin†

Ekaterina S. Sazanova,^a Iuliia A. Gracheva,

^a Diane Allegro,^b Pascale Barbier,^b Sébastien Combes,^cd Elena V. Svirshchevskaya

^e and Alexey Yu Fedorov

*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry, N. I. Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Avenue, 603950 Nizhny Novgorod, Russian Federation

^b Institute of NeuroPhysiopathology (INP) – CNRS UMR 7051, Aix-Marseille University, 27 Boulevard Jean Moulin, 13385 Marseille, Cedex 5, France

^c CRCM, CNRS, Inserm, Institut Paoli-Calmettes, Aix-Marseille University, 232 Boulevard de Sainte-Marguerite, 13009 Marseille, France

^d DOSynth Platform, CRCM, Faculté de Pharmacie, Aix-Marseille Université, 27 Boulevard Jean Moulin, 13385 Marseille, Cedex 5, France

^e Laboratory of Cell Interactions, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 16/10 Miklukho-Maklaya Street, 117997 Moscow, Russian Federation

Abstract

We describe an attempt to apply the concept of covalent binding towards the highly active allocolchicinoids selected on the basis of SAR analysis of previously synthesized molecules. To achieve the irreversible binding of the agent to the cysteine residues of the colchicine site of tubulin protein, we synthesized a number of new allocolchicinoids bearing the acceptor moiety. Some of the new derivatives possess cytotoxic activity against COLO-357, BxPC-3, HaCaT, and HEK293 cell lines in a low nanomolar range of concentrations. A substoichiometric mode of microtubule assembly inhibition was demonstrated. The most active compounds possess close to colchicine general toxicity on mice.

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DOI: https://doi.org/10.1039/D0MD00060D
Article type: Research Article
Submitted: 22 Feb 2020
Accepted: 10 Apr 2020
First published: 04 Jun 2020

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RSC Med. Chem., 2020,11, 696-706

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Allocolchicinoids bearing a Michael acceptor fragment for possible irreversible binding of tubulin

E. S. Sazanova, I. A. Gracheva, D. Allegro, P. Barbier, S. Combes, E. V. Svirshchevskaya and A. Y. Fedorov, RSC Med. Chem., 2020, 11, 696 DOI: 10.1039/D0MD00060D

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RSC Medicinal Chemistry

Allocolchicinoids bearing a Michael acceptor fragment for possible irreversible binding of tubulin†

Abstract

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Allocolchicinoids bearing a Michael acceptor fragment for possible irreversible binding of tubulin

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