Progress in electron transfer reactions of new quinone bioreductive alkylating agents

As bioreductive alkylating agents, quinones constitute good substrates for single or multiple electron transfer reactions (S RN 1, bis-S RN 1 or tetra-S RN 1) leading to original and highly substituted benzoquinone, naphthoquinone and anthraquinone derivatives, potential anticancer agents. Quinones are versatile organic compounds endowed with rich and fascinating chemistry. Many of them are important therapeutic agents (1), quite often they serve as auxiliaries in organic synthesis and in the dye industry (2). Quinones, and particularly anthracyclines (as doxorubicin and daunorubicin) or mitomycins (as mitomycin C) as shown in Scheme 1 are important antitumor agents presenting a clinical effectiveness against many types of human cancers. However, intrinsic and acquired drug resistance and undesired effects such as cumulative dose-dependent cardiotoxicity limit their clinical utilization (3). The term, bioreductive alkylation (1) is used to explain the mode of action of these antitumor antibiotics. The quinone alkylating agent by one or two electron reductive activation loses a leaving group to form a reactive intermediate named quinone methide. Nucleophilic attack by DNA produces an appropriate adduct which is oxidized by the quinone or dioxygen to give an alkylated DNA. So, the modification of DNA leads to the death of tumor cells, the quinone alkylating agent expressing its antitumor effect. Superoxide and other active oxygen species may induce undesirable cytotoxic effects such damage to heart (Scheme 2). The number of electrons which must be given to the quinone for this process poses a very difficult mechanistic problem (4). In fact, after one or two electron activation, many equilibria are possible as demonstrated in Scheme 3 and three quinone methide forms may be produced: an ionic form, a neutral form or a radical form Mitomycin C has been shown to be an inhibitor of the synthesis of nucleic acids(...)