Synthesis And Cytotoxicity Mechanism Study Of Halogenated Binaphthoquinones

Killing cancer cell via elevation of reactive oxygen species (ROS) has recently attracted much attention. Hydroxyl radicals are considered to be the most harmful ROS to cells. Transition metal-catalyzed Fenton reaction is a widely accepted mechanism of hydroxyl radical production. Zhu et al have found another mechanism for metal-independent production of hydroxyl radicals:a nucleophilic attack of H2O2 to halogenated quinones, forming a hydroperoxide intermediate, which decomposes homolytically to produce hydroxyl radicals (Proc. Natl. Acad. Sci.USA 2007,104, 17575). This mechanism motivated us to design a few halogenated quinines and observe whether they can make use of high level H2O2 of cancer cells to produce high toxic hydroxyl radicals and thus kill cancer cells. Inspired by conocurvone, a natural product, we designed and synthesized a series of halogenated binaphthoquinones based on its mother nucleus structure. The main contents are as follows:(1) Halogenated binaphthoquinones (BQ-HC, BQ-HB and BQ-DC) could significantly inhibit HepG2 cell growth with the IC50 values being 1.99,2.20 and 8.14 μM, respectively. In contrast, their cytotoxicity is significantly weakened in L02 cells. Furthermore, we confirm by in vitro experiments that halogenated binaphthoquinones could react with H2O2 to produce hydroxyl radicals, and also react with GSH and covalently modify thioredoxin reductase (TrxR), that are probably responsible for their cytotoxicity.(2) A cooperation of halogenated binaphthoquinones and H2O2 could synergistically induce DNA damage, membrane lipid peroxidation and death of A549 cells.