Highly Potent Triazole-Based Tubulin Polymerization Inhibitors

• Published in: Journal of medicinal chemistry Vol. 50; no. 4; pp. 749 - 754
• Main Authors: Zhang, Qiang, Peng, Youyi, Wang, Xin I, Keenan, Susan M, Arora, Sonia, Welsh, William J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.02.2007; Amer Chemical Soc
• Subjects: Antineoplastic agents; Biological and medical sciences; Biopolymers; Cell Line, Tumor; Chemistry, Medicinal; Crystallography, X-Ray; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; COMBRETASTATIN A-4 ANALOGS; MOLECULAR-DYNAMICS; COLCHICINE; ANTITUBULIN AGENTS; CHARGES; RESISTANCE; BINDING-SITE; CELL-LINES; DIELECTRIC MEDIUM; DISCOVERY; Antineoplastic agent; Human; Solid tumor; Squamous cell carcinoma; Antitubulin; Cytotoxicity; Uterine cervix; In vitro; Hela cell line; Cell line; Structure activity relation; Multiple resistance; Triazole derivatives; Colon; Mammary gland; Indole derivatives; Chemical synthesis; Antimitotic; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061142s

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.