Discovery of a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by scaffold modification
Journal
Journal of Medicinal Chemistry
Journal Volume
52
Journal Issue
18
Pages
5649-5661
Date Issued
2009
Author(s)
Abstract
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. ? 2009 American Chemical Society.
SDGs
Other Subjects
1 ethyl 3 (6 nitrobenzoxazol 2 yl) 6,8 difluoro 7 (3 methylpiperazin 1 yl) 4(1h) quinolone; antineoplastic agent; camptothecin; DNA; DNA topoisomerase inhibitor; naphthyridine derivative; quinolone derivative; scaffold protein; unclassified drug; animal experiment; animal tissue; antineoplastic activity; apoptosis; article; cancer cell culture; cancer cell destruction; cell cycle regulation; cell proliferation; cell strain HT29; cell viability; colony formation; controlled study; DNA content; DNA strand breakage; dose response; drug cytotoxicity; drug design; drug DNA binding; drug mechanism; drug screening; drug synthesis; enzyme inhibition; female; human; human cell; IC 50; mouse; nonhuman; nude mouse; protein cleavage; protein expression; structure activity relation; tumor xenograft; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; DNA; Drug Discovery; Enzyme Inhibitors; Female; Humans; Mice; Mice, Nude; Models, Molecular; Molecular Conformation; Naphthyridines; Neoplasms; Quinolones; Topoisomerase I Inhibitors; Transplantation, Heterologous
Type
journal article