2. Academic Validation
  3. Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers

Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers

  • Eur J Med Chem. 2018 Feb 10:145:498-510. doi: 10.1016/j.ejmech.2018.01.010.
Peng-Hui Li 1,  Hong Jiang 1,  Wen-Jin Zhang 1,  Yong-Lian Li 1,  Min-Cong Zhao 1,  Wei Zhou 1,  Lan-Yue Zhang 1,  Ya-Dong Tang 1,  Chang-Zhi Dong 2,  Zhi-Shu Huang 3,  Hui-Xiong Chen 4,  Zhi-Yun Du 5
Affiliations

Affiliations

  • 1 Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, 510006, China.
  • 2 Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, 510006, China; Universite Paris Diderot, Sorbonne Paris Cite, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baif, 75270, Pairs Cedex 13, France.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 4 Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, 510006, China; CNRS, UMR8601, Laboratoire de Chimine et Biochimie Pharmacologiques et Toxicologiques, CBNIT, Universite Paris Descartes PRES Sorbonne Paris Cite, UFR Bio5medicale, 45 rue des Saints-Peres, 75270, Paris Cedex 06, France.
  • 5 Institute of Natural Medicine & Green Chemistry, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, 510006, China. Electronic address: zhiyundu@gdut.edu.cn.
PMID: 29335211 DOI: 10.1016/j.ejmech.2018.01.010
Abstract

Novel Topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of Anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity. Further mechanism studies revealed that CDCAs function as non-intercalative Topo II catalytic inhibitors. Moreover, some CDCAs showed micromolar cytotoxic activities. The most potent compound 3h exhibited notable growth inhibition against four human Cancer cell lines. Flow cytometric analysis revealed that compounds 3d and 3h arrested the HL-60 cells in sub G1 phase by induction of Apoptosis. It was further confirmed by Annexin-V-FITC binding assay. Western blot analysis revealed that compound 3h induces Apoptosis likely through the activation of Caspase proteins.

Keywords

Apoptosis; Carbazole; Chalcone; Cytotoxic; Topoisomerase II.

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