Novel 2-Substituted Quinolin-4-yl-benzenesulfonate Derivatives: Synthesis, Antiproliferative Activity, and Inhibition of Cellular Tubulin Polymerization

• Published in: ChemMedChem Vol. 6; no. 6; pp. 1119 - 1129
• Main Authors: Kakadiya, Rajesh, Wu, Yi-Chen, Dong, Huajin, Kuo, Hsiao-Hui, Yih, Ling-Huei, Chou, Ting-Chao, Su, Tsann-Long
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 06.06.2011; WILEY‐VCH Verlag
• Subjects: 4-Quinolones - chemistry; 4-Quinolones - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agents; Apoptosis - drug effects; Benzenesulfonates - chemistry; Benzenesulfonates - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; cytotoxicity; Drug Screening Assays, Antitumor; Humans; Mitosis - drug effects; mitotic arrest; Neoplasms - drug therapy; sulfonates; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; tubulin polymerization
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201100121

A series of 2‐substituted quinolin‐4‐yl‐benzenesulfonate derivatives were synthesized for the purpose of evaluating antiproliferative activity. Structure–activity relationships of the newly synthesized compounds against human lymphoblastic leukemia and various solid tumor cell growths in culture are discussed. Of these derivatives, 2‐phenyl‐6‐pyrrolidinyl‐4‐quinoline sulfonate analogues 10 f, 10 g, and 10 k, and 4′‐nitrophenyl sulfonate 10 m exhibit superior cytotoxicity over other sulfonates. The antiproliferative activities of these compounds correlate well with their abilities to induce mitotic arrest and apoptosis. Mechanistic studies indicate that they target the vinblastine binding site of tubulin and inhibit cellular tubulin polymerization. Hence, these compounds induce the formation of aberrant mitotic spindles and mitotic arrest, resulting in intensive apoptosis. The tested compounds were shown to be poor substrates for membrane multidrug resistance transporters. The present studies suggest that these newly synthesized compounds are promising tubulin polymerization inhibitors and are worthy of further investigation as antitumor agents. When everything falls apart: A series of 2‐substituted quinolin‐4‐yl‐benzenesulfonates were synthesized and found to have significant cytotoxicity against various human tumor cell growths. Mechanistic studies revealed that these agents are able to interfere with the assembly of mitotic spindles and block the progression of mitosis. Moreover, these compounds bind to the vinblastine binding site of tubulin, thereby inhibiting tubulin polymerization.