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
Affiliations
  • 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.