Antitumor agents 288: Design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents

Xiaoming Yang, Qian Shi, Shuenn Chen Yang, Chi Yuan Chen, Sung Liang Yu, Kenneth F. Bastow, Susan L. Morris-Natschke, Pei Chi Wu, Chin Yu Lai, Tian Shung Wu, Shiow Lin Pan, Che Ming Teng, Jau Chen Lin, Pan Chyr Yang, Kuo Hsiung Lee

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30 Citations (Scopus)

Abstract

Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI 50: 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.

Original languageEnglish
Pages (from-to)5097-5107
Number of pages11
JournalJournal of Medicinal Chemistry
Volume54
Issue number14
DOIs
Publication statusPublished - Jul 28 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Yang, X., Shi, Q., Yang, S. C., Chen, C. Y., Yu, S. L., Bastow, K. F., Morris-Natschke, S. L., Wu, P. C., Lai, C. Y., Wu, T. S., Pan, S. L., Teng, C. M., Lin, J. C., Yang, P. C., & Lee, K. H. (2011). Antitumor agents 288: Design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents. Journal of Medicinal Chemistry, 54(14), 5097-5107. https://doi.org/10.1021/jm200330s