Colchicine derivatives with potent anticancer activity and reduced P-glycoprotein induction liability

Colchicine(1), a nature-derived microtubule polymerizationinhibitor, develops multi-drug resistance in tumor cells due to its P-gp substrate and inductionactivity, which in turn leads to its rapid efflux from tumor cells. This auto- inductionof the efflux of colchicineremains a major challenge to medicinal chemists. Based on structure-based molecular modeling, a series of new colchicinederivatives were designed and synthesized with a potential for reduced P-gp inductionliability. Screening of the prepared derivatives for P-gp inductionactivity revealed that a number of derivatives possess remarkably lower P-gp- inductionactivity (>90% intracellular accumulation of rhodamine 123in LS-180 cells) compared to the parent natural product colchicine(62% Rh123 accumulation in LS-180 cells). The reduced P-gp- inductionactivity of new derivatives may be due to their reduced ability to interact and change the conformation of P-gp. The synthesized derivatives were then screened for antiproliferative activity against two colon cancer cell lines including HCT-116 and Colo-205. The derivative 4o showed potent cytotoxicity in HCT-116 cells with IC50 of 0.04 μM with significantly reduced P-gp inductionliability. Compound 4o also inhibited microtubule assembly and induced expression of pro-apoptotic protein p21. In an Ehrlich solid tumor mice model, compound 4o showed 38% TGI with no mortality at 2 mg kg−1 dose (oral). Compound 4o, with potent in vitro and in vivo anticancer activity, significantly reduced P-gp inductionactivity and its excellent physicochemical and pharmacokinetic properties open up new opportunities for the colchicinescaffold.