| Autor: |
Singh B; Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India., Kumar A, Joshi P, Guru SK, Kumar S, Wani ZA, Mahajan G, Hussain A, Qazi AK, Kumar A, Bharate SS, Gupta BD, Sharma PR, Hamid A, Saxena AK, Mondhe DM, Bhushan S, Bharate SB, Vishwakarma RA |
| Jazyk: |
angličtina |
| Zdroj: |
Organic & biomolecular chemistry [Org Biomol Chem] 2015 May 28; Vol. 13 (20), pp. 5674-89. Date of Electronic Publication: 2015 Apr 21. |
| DOI: |
10.1039/c5ob00406c |
| Abstrakt: |
Colchicine (1), a nature-derived microtubule polymerization inhibitor, develops multi-drug resistance in tumor cells due to its P-gp substrate and induction activity, which in turn leads to its rapid efflux from tumor cells. This auto-induction of the efflux of colchicine remains a major challenge to medicinal chemists. Based on structure-based molecular modeling, a series of new colchicine derivatives were designed and synthesized with a potential for reduced P-gp induction liability. Screening of the prepared derivatives for P-gp induction activity revealed that a number of derivatives possess remarkably lower P-gp-induction activity (>90% intracellular accumulation of rhodamine 123 in LS-180 cells) compared to the parent natural product colchicine (62% Rh123 accumulation in LS-180 cells). The reduced P-gp-induction activity 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 induction liability. 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 induction activity and its excellent physicochemical and pharmacokinetic properties open up new opportunities for the colchicine scaffold. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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