Cytocidal action of the quinone group and its relationship to antitumor activity

Many clinically useful antitumor agents have a quinone group in their structure. A series of model compounds has been studied to determine if the quinone group is involved in the cytotoxic activity of these agents and to investigate the mechanism of this action. Hydrolyzed benzoquinone mustard, which contains a quinone group, produced significant cell kill of L5178Y lymphoblasts, whereas hydrolyzed aniline mustard, which has a similar chemical structure but contains no active functional groups, showed little activity against this cell line. Benzoquinone mustard, which possesses both a quinone moiety and an active alkylating group, was approximately 30,000 times more active against L5178Y cells than was hydrolyzed benzoquinone mustard. It was approximately 600 times more active than aniline mustard, a compound which has the same alkylating group but no quinone function, and 200 times more active than an equimolar combination of aniline mustard and hydrolyzed benzoquinone mustard. The cytotoxic activity of hydrolyzed benzoquinone mustard was inhibited by either superoxide dismutase or catalase, while catalase but not superoxide dismutase inhibited the activity of benzoquinone mustard. Neither enzyme had any effect on the cytocidal action of aniline mustard. These studies suggest that the presence of a quinone group in the chemical structure of a compound can result in significant cell kill by a mechanism that appears to involve free radicals and active oxygen species. In addition, if the compound contains an alkylating group which can bind to DNA, as well as a quinone moiety, the cytocidal activity of the agent appears to be enhanced and is greater than that resulting from an additive effect of the two groups.