Synthesis and biological evaluation of colchicine C-ring analogues tethered with aliphatic linkers suitable for prodrug derivatisation

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7693-6. doi: 10.1016/j.bmcl.2012.09.104.

Jérémie Fournier-Dit-Chabert ¹, Victoria Vinader, Ana Rita Santos, Mariano Redondo-Horcajo, Aurore Dreneau, Ramkrishna Basak, Laura Cosentino, Gemma Marston, Hamdy Abdel-Rahman, Paul M Loadman, Steven D Shnyder, José Fernando Díaz, Isabel Barasoain, Robert A Falconer, Klaus Pors

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Affiliation

1 Institute of Cancer Therapeutics, University of Bradford, BD7 1DP, UK.

PMID: 23103097 DOI: 10.1016/j.bmcl.2012.09.104

Abstract

Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon Cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.

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