Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents

Mei Juan Wang, Ying Qian Liu, Ling Chu Chang, Chih Ya Wang, Yong Long Zhao, Xiao Bo Zhao, Keduo Qian, Xiang Nan, Liu Yang, Xiao Ming Yang, Hsin Yi Hung, Jai Sing Yang, Daih Huang Kuo, Masuo Goto, Susan L. Morris-Natschke, Shiow Lin Pan, Che Ming Teng, Sheng Chu Kuo, Tian Shung Wu, Yang Chang WuKuo Hsiung Lee

研究成果: 雜誌貢獻文章

45 引文 斯高帕斯(Scopus)

摘要

Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.
原文英語
頁(從 - 到)6008-6018
頁數11
期刊Journal of Medicinal Chemistry
57
發行號14
DOIs
出版狀態已發佈 - 七月 24 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Wang, M. J., Liu, Y. Q., Chang, L. C., Wang, C. Y., Zhao, Y. L., Zhao, X. B., Qian, K., Nan, X., Yang, L., Yang, X. M., Hung, H. Y., Yang, J. S., Kuo, D. H., Goto, M., Morris-Natschke, S. L., Pan, S. L., Teng, C. M., Kuo, S. C., Wu, T. S., ... Lee, K. H. (2014). Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents. Journal of Medicinal Chemistry, 57(14), 6008-6018. https://doi.org/10.1021/jm5003588