title: Highly potent triazole-based tubulin polymerization inhibitors.
abstract: We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors that contain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond in combretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerization inhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant (MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, as exemplified by compound 7, conferred optimal properties among this series. Computer docking and molecular simulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likely to interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It is hoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles as potential anti-cancer therapeutic agents.
authors.affiliation: Department of Pharmacology, University of Medicine & Dentistry of New Jersey, Robert Wood Johnson Medical School, and Informatics Institute of the University of Medicine & Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Youyi
authors.initials: Y
authors.lastname: Peng
authors.forename: Xin I
authors.initials: XI
authors.lastname: Wang
authors.forename: Susan M
authors.initials: SM
authors.lastname: Keenan
authors.forename: Sonia
authors.initials: S
authors.lastname: Arora
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
mesh_terms: D001704:Biopolymers; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001704:Biopolymers; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators