title: Colchicine derivatives with potent anticancer activity and reduced P-glycoprotein induction liability.
abstract: 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.
authors.affiliation: Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Baljinder
authors.initials: B
authors.lastname: Singh
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Guru
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.forename: Zahoor A
authors.initials: ZA
authors.lastname: Wani
authors.forename: Girish
authors.initials: G
authors.lastname: Mahajan
authors.forename: Aashiq
authors.initials: A
authors.lastname: Hussain
authors.forename: Asif Khurshid
authors.initials: AK
authors.lastname: Qazi
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.forename: Sonali S
authors.initials: SS
authors.lastname: Bharate
authors.forename: Bishan D
authors.initials: BD
authors.lastname: Gupta
authors.forename: Parduman R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Saxena
authors.forename: Dilip M
authors.initials: DM
authors.lastname: Mondhe
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000378:metabolism*; D000081:Acetamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D011487:Protein Conformation; D014018:Tissue Distribution; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000081:Acetamides; D000970:Antineoplastic Agents; C000605115:N-(1,2,3-trimethoxy-9-oxo-10-(3-(trifluoromethyl)-4-chlorophenylamino)-5,6,7,9-tetrahydrobenzo(a)heptalen-7-yl)acetamide; D050257:Tubulin Modulators; D003078:Colchicine