1. Synthesis and biological evaluation of 4-phenyl-5-quinolinyl substituted isoxazole analogues as potent cytotoxic and tubulin polymerization inhibitors against ESCC.
- Author
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Jia M, Pei Y, Li N, Zhang Y, Song J, Niu JB, Yang H, Zhang S, and Sun M
- Subjects
- Animals, Humans, Mice, Apoptosis drug effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Molecular Structure, Polymerization drug effects, Quinolines pharmacology, Quinolines chemistry, Quinolines chemical synthesis, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Esophageal Neoplasms drug therapy, Esophageal Neoplasms pathology, Esophageal Neoplasms metabolism, Esophageal Squamous Cell Carcinoma drug therapy, Esophageal Squamous Cell Carcinoma pathology, Esophageal Squamous Cell Carcinoma metabolism, Isoxazoles pharmacology, Isoxazoles chemistry, Isoxazoles chemical synthesis, Tubulin metabolism, Tubulin Modulators pharmacology, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry
- Abstract
The identification of chemically different inhibitors that target the colchicine site of tubulin is still of great value for cancer treatment. Combretastatin A-4(CA-4), a naturally occurring colchicine-site binder characterized by its structural simplicity and biological activity, has served as a structural blueprint for the development of novel analogues with improved safety and therapeutic efficacy. In this study, a library of forty-eight 4-phenyl-5-quinolinyl substituted triazole, pyrazole or isoxazole analouges of CA-4, were synthesized and evaluated for their cytotoxicity against Esophageal Squamous Cell Carcinoma (ESCC) cell lines. Compound C11, which features a 2-methyl substitution at the quinoline and carries an isoxazole ring, emerged as the most promising, with 48 h IC
50 s of less than 20 nmol/L against two ESCC cell lines. The findings from EBI competitive assay, CETA, and in vitro tubulin polymerization assay of C11 are consistent with those of the positive control colchicine, demonstrating the clear affinity of compound C11 to the colchicine binding site. The subsequent cellular-based mechanism studies revealed that C11 significantly inhibited ESCC cell proliferation, arrested cell cycle at the M phase, induced apoptosis, and impeded migration. Experiments conducted in vivo further confirmed that C11 effectively suppressed the growth of ESCC without showing any toxicity towards the selected animal species. Overall, our research suggests that the tubulin polymerization inhibitor incorporating quinoline and the isoxazole ring may deserve consideration for cancer therapy., Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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