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.

Natsumi Suematsu ¹, Masayuki Ninomiya ¹, Hodaka Sugiyama ¹, Taro Udagawa ¹, Kaori Tanaka ², Mamoru Koketsu ³

Affiliations

1 Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
2 Division of Anaerobe Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; United Graduate School of Drug Discovery and Medicinal Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
3 Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: koketsu@gifu-u.ac.jp.

PMID: 31253531 DOI: 10.1016/j.bmcl.2019.06.038

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.

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