Exerting DNA Damaging Effects of the Ilimaquinones through the Active Hydroquinone Species

Abstract

Possessing the quinone moiety, ilimaquinone (1), a sponge–derived sesquiterpene quinone, has been hypothesised to express its cytotoxicity through a redox cycling process, yielding active product(s) that can cause DNA damage. To determine the DNA damaging effects of 1 and examine whether a redox transformation may participate in its functions, the DNA damaging properties of 1, the corresponding hydroquinone (2) and hydroquinone triacetates (3) and their 5-epimeric counterparts (4–6) were tested and compared. When incubated directly with plasmid DNA, the hydroquinones were the only active species capable of cleaving the DNA. In cell-based assays, however, the quinones and hydroquinone triacetates were active in the same range as that of the corresponding hydroquinones, and all damaged the cellular DNA in a similar manner. The in situ reduction of 1 and 4 were supported by the decreases in the cytotoxicity when cells were pre-exposed to dicoumarol, an NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitor. The results confirmed the DNA damaging activities of the ilimaquinones 1 and 4, and indicated the necessity to undergo an in-situ transformation into the active hydroquinones, thereby exerting the DNA damaging properties as parts of the cytotoxic mechanisms.

Keywords

• sesquiterpene quinones
• cytotoxicity
• redox cycling
• marine natural products