Synthesis of carbazoloquinone derivatives and their antileukemic activity via modulating cellular reactive oxygen species

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2243-2247. doi: 10.1016/j.bmcl.2019.06.038. Epub 2019 Jun 20.

Abstract

Carbazoloquinone alkaloids are of great interest as privileged structures for anticancer drug molecules. The purpose of this study was to investigate the structure-activity relationships of carbazoloquinone derivatives as anticancer agents. A series of carbazoloquinones including murrayaquinone A, koeniginequinones A and B, and related analogues were therefore prepared. Palladium-catalyzed intramolecular cyclization reaction mechanism was well elucidated by DFT calculations. Treatment of the synthesized derivatives showed cytotoxicity on human leukemia HL-60 cells in a dose-dependent fashion. In addition, murrayaquinone A and β-brazanquinone elevated cellular levels of reactive oxygen species (ROS), thereby triggering apoptosis. Our findings emphasize the excellent potential of carbazoloquinone derivatives as ROS-inducing anticancer agents.

Keywords: Apoptosis; Carbazoloquinone alkaloid; DFT calculation; Murrayaquinone A; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzoquinones / chemical synthesis
  • Benzoquinones / chemistry
  • Benzoquinones / pharmacology*
  • Carbazoles / chemical synthesis
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Density Functional Theory
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HL-60 Cells
  • Humans
  • Molecular Structure
  • Reactive Oxygen Species / metabolism*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzoquinones
  • Carbazoles
  • Reactive Oxygen Species
  • carbazole
  • quinone