Synthesis and biological evaluation of N(9)-substituted harmine derivatives as potential anticancer agents

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4015-9. doi: 10.1016/j.bmcl.2016.06.087.

Hongtao Du ¹, Shan Tian ², Juncheng Chen ³, Hongling Gu ⁴, Na Li ⁵, Junru Wang ⁶

Affiliations

1 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China; College of Plant Protection, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China. Electronic address: duht@nwsuaf.edu.cn.
2 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China. Electronic address: stian@nwsuaf.edu.cn.
3 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China. Electronic address: cjc2009@nwsuaf.edu.cn.
4 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China. Electronic address: hlgu@nwsuaf.edu.cn.
5 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China. Electronic address: lnuk@nwsuaf.edu.cn.
6 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China. Electronic address: wangjunru@nwsuaf.edu.cn.

PMID: 27397495 DOI: 10.1016/j.bmcl.2016.06.087

Abstract

A series of N(9)-substituted harmine derivatives were synthesized and evaluated for their Anticancer activity on a panel of Cancer cell lines, their Apoptosis induction and their cell cycle effects. The results showed that N(9)-substituted harmine derivatives had Anticancer effects. In particular, N(9)-haloalkyl derivatives 9a-9c and N(9)-acyl harmine derivatives 11c and 11d, with IC50 values less than 1μM, were more potent than doxorubicin against A-549 and/or MCF-7 cell lines. Moreover, structure-activity relationships (SARs) indicated that introducing a haloalkyl or benzenesulfonyl group in the N(9)-position of harmine could significantly increase the Anticancer activity. The most active compound (11d) caused cell cycle arrest in the G2/M phase, and induced cell Apoptosis in a dose-dependent manner.

Keywords

Anticancer activities; Apoptosis; Cell cycle arrest; Harmine derivatives; Structure–activity relationships (SARs).

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