Discovery of a Novel Series of Quinolone and Naphthyridine Derivatives as Potential Topoisomerase I Inhibitors by Scaffold Modification

A novel series of topoisomerase I (Top I) inhibitors were designed on the basis of camptothecin using scaffold modification strategy. Thirty-one new compounds were synthesized and evaluated for anticell proliferation activity. The most potent compound 26 presented a significant inhibitory effect on...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-09, Vol.52 (18), p.5649-5661
Main Authors: You, Qi-Dong, Li, Zhi-Yu, Huang, Chiung-Hua, Yang, Qian, Wang, Xiao-Jian, Guo, Qing-Long, Chen, Xiao-Guang, He, Xun-Gui, Li, Tsai-Kun, Chern, Ji-Wang
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
DNA - metabolism
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Female
General aspects
Humans
Medical sciences
Mice
Mice, Nude
Models, Molecular
Molecular Conformation
Naphthyridines - chemistry
Naphthyridines - pharmacology
Naphthyridines - therapeutic use
Neoplasms - drug therapy
Neoplasms - pathology
Pharmacology. Drug treatments
Quinolones - chemistry
Quinolones - pharmacology
Quinolones - therapeutic use
Topoisomerase I Inhibitors
Transplantation, Heterologous
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Summary:A novel series of topoisomerase I (Top I) inhibitors were designed on the basis of camptothecin using scaffold modification strategy. Thirty-one new compounds were synthesized and evaluated for anticell proliferation activity. The most potent compound 26 presented a significant inhibitory effect on Top I, leading to Top I-mediated cleavage and influences on Top I expression at the cellular level. Moreover, 26 was proved to induce cell death via apoptosis and accelerated DNA strand breaks without significant alteration in cell cycle populations. All of the experimental results herein indicated that 26 could interact with DNA−Top I complex and induce cancer cell apoptosis to produce antitumor effects. The in vivo evaluation of 26 on the growth of HT-29 tumor xenografts in nude mice suggested its therapeutic potential for further development.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900469e