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 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.
You
Qi-Dong
QD
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. youqidong@gmail.com
Li
Zhi-Yu
ZY
Huang
Chiung-Hua
CH
Yang
Qian
Q
Wang
Xiao-Jian
XJ
Guo
Qing-Long
QL
Chen
Xiao-Guang
XG
He
Xun-Gui
XG
Li
Tsai-Kun
TK
Chern
Ji-Wang
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D015363:Quinolones; D059004:Topoisomerase I Inhibitors; D004247:DNA