1. Academic Validation
  2. Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3

Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3

  • Medchemcomm. 2019 Feb 25;10(3):465-477. doi: 10.1039/c8md00624e.
Junjie Ma 1 Xin Ni 1 Yali Gao 2 Kun Huang 1 Jiaan Liu 3 Yu Wang 1 Roufen Chen 1 Cuifang Wang 4
Affiliations

Affiliations

  • 1 School of Medicine , Huaqiao University , Quanzhou , 362000 , China . Email: majunjie3612@hqu.edu.cn.
  • 2 Pharmacy Department , The Second Affiliated Hospital of Fujian Medical University , Quanzhou , 362000 , China.
  • 3 Department of Chemistry , University of Massachusetts-Amherst , Amherst , Massachusetts 01003 , USA.
  • 4 College of Oceanology and Food Science , Quanzhou Normal University , Quanzhou 362000 , China . Email: wlycf@163.com.
Abstract

Three series of compounds were designed, synthesized and evaluated for their in vitro Anticancer activity against a procaspase-3 over-expression Cancer cell line (U937) and a procaspase-3 no-expression Cancer cell line (MCF-7) to rule out off-target effects. Biological evaluation led to the identification of a series of benzothiazole derivatives bearing a pyridine-semicarbazone moiety, 8j and 8k, with promising Anticancer activity and remarkable selectivity. Further mechanism studies revealed that compounds 8j and 8k could induce Apoptosis of Cancer cells by activating procaspase-3 to Caspase-3, and compound 8k exhibited the strongest procaspase-3 activation activity. Structure-activity relationships (SARs) revealed that the presence of benzothiazole and an N,N,O-donor set is crucial for the Anticancer activity and selectivity, and reducing the electron density of the N,N,O-donor set results in a dramatic decline in the Anticancer activity and selectivity. Furthermore, toxicity evaluation (zebrafish) in vivo and metabolic stability studies (human, rat and mouse liver microsomes) were performed to provide reliable guidance for further PK/PD studies in vivo.

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