1. Synthesis of carbazole derivatives containing chalcone analogs as non-intercalative topoisomerase II catalytic inhibitors and apoptosis inducers.
- Author
-
Li PH, Jiang H, Zhang WJ, Li YL, Zhao MC, Zhou W, Zhang LY, Tang YD, Dong CZ, Huang ZS, Chen HX, and Du ZY
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Biocatalysis, Carbazoles chemical synthesis, Carbazoles chemistry, Cell Cycle Checkpoints drug effects, Cell Proliferation drug effects, Chalcone chemistry, DNA Cleavage drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HL-60 Cells, Humans, Molecular Structure, Plasmids, Structure-Activity Relationship, Topoisomerase II Inhibitors chemical synthesis, Topoisomerase II Inhibitors chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Carbazoles pharmacology, Chalcone pharmacology, DNA Topoisomerases, Type II metabolism, Topoisomerase II Inhibitors pharmacology
- 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., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF