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

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.

SUBMITTER: Sazanova ES

PROVIDER: S-EPMC7578708 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Sazanova Ekaterina S ES Gracheva Iuliia A IA Allegro Diane D Barbier Pascale P Combes Sébastien S Svirshchevskaya Elena V EV Fedorov Alexey Yu AY

RSC medicinal chemistry 20200604 6

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 nan ...[more]

PMID: 33479669

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