FIGURE 11.8 Reductive generation of electrophilic quinone methides from quinones.

After reduction, these compounds generate highly reactive quinone methides that behave as DNA alkylators (Fig. 11.8).

Two simple examples of antitumor compounds designed using this strategy are quinones 11.19 and 11.2,10 though they show only a marginal hypoxic selectivity. The natural products mitomycin C and porfiromycin are also activated by bioreductive mechanisms (see Section 3 of Chapter 6).

The second structural type of bioreductively activated quinones is aziridinyl-quinones, represented by the benzoquinone derivative diaziquone and by indo-lequinone EO-9 (see also Section 3 of Chapter 5). These quinones are bioactivated by two-electron reductases, particularly DT-diaphorase (Fig. 11.9), an enzyme that is overexpressed in many tumors, but their clinical results have not been particularly successful.

A final application of quinones in bioreductive activation processes is their use as triggers for the release of alkylating species, especially nitrogen mustards. One example is compound 11.3, which liberates a molecule of melphalan upon lacto-nization of its reduced hydroquinone form (see also Section 2.4 of Chapter 5). In the case of 11.4, reduction to hydroquinone is followed by C-N bond cleavage to release the aliphatic mustard 11.5. This reaction is not possible before the reduction step because of the electron-withdrawing effect of the quinone moiety on the indole nitrogen (Fig. 11.10).

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