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.
Highlights
Quinone and hydroquinone moieties have long been appreciated as ones of the biologically active functionalities, especially in the anticancer-antitumor chemotherapy
Upon being reduced to the corresponding hydroquinone, an autoxidation back to the parent structure of the quinone resulted in the reactive oxygen species that can cause the oxidative stress and cell death
Several marine-derived sesquiterpene quinones have been hypothesised to express parts of their cytotoxic mechanisms through the in situ redox cycling on the quinone functionalities, which leads to reactive products that could cause DNA damages
Summary
Quinone and hydroquinone moieties have long been appreciated as ones of the biologically active functionalities, especially in the anticancer-antitumor chemotherapy. Centering on the cytotoxicity of quinone/hydroquinone functionalities, two mechanisms—both of which involve the interconversion between the quinone and hydroquinone species through a redox cycling process—have been proposed. Quinone and quinonoid moieties can alkylate onto biological nucleophiles after being reduced into the hydroquinone and/or semiquinone radical. This is the primary mechanism associated with the anticancer activity of mitomycin C [1]. Upon being reduced to the corresponding hydroquinone, an autoxidation back to the parent structure of the quinone resulted in the reactive oxygen species that can cause the oxidative stress and cell death. Diaziquone exerts the anticancer activity, in part through this autoxidation pathway [2]
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