Bioreductive Alkylation — Naturally Occurring Quinones as Potential Candidates

Abstract

Bioreductive alkylation is the term used to describe the effect of those compounds which express their mode of biological action as alkylating agents, but do so subsequent to their in vivo reduction.1 That is, they are pro-drugs which are activated by a bioreduction. A class of compounds ideally suited to function as the reducible moiety of bioreductive alkylating agents is the quinones since their facile in vivo and in vitro reduction to the corresponding hydroquinones is a well known and extensively studied reaction.2 If the quinone is further substituted with a side-chain bearing a leaving group (X) at the 2-position of the substituent, then quinone methide formation can result by an elimination of HX from the hydroquinone.3 The reactive quinone methide is suggested as the discrete alkylating agent and functions as such by a Michael addition of a biologically important nucleophile (Nu−: DNA, protein, carbohydrate, etc.) to the enone of the methide. This postulate is represented by the sequence of reactions outlined in Scheme 1, i.e., 1 → 2 → 3 →4. Further comments concerning the details of this proposed mechanism of action follow. 1) Although a two-electron reduction is represented, a one-electron process can also be envisaged. That is, rather than the hydroquinone 2, a semiquinone radical-anion could be formed initially. This could then proceed to the radical form of 3 and subsequently to a radical anion of 4. 2) The facility of quinone methide formation, and thus biological activity, may be enhanced as the half-wave reduction potential (E1/2) of the quinone decreases.