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

[摘要] Colchicine was modified at the 10-OCH3 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 beta-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery. (C) 2012 Elsevier Ltd. All rights reserved.

[发布日期] 2012-12-15

[关键词] Colchicine;MDR (ABCB1, P-glycoprotein);Class III beta-tubulin resistance;Prodrug;Matrix metalloproteinases (MMPs)