NITRO REDUCTION AS AN ELECTRONIC SWITCH FOR BIOREDUCTIVE DRUG ACTIVATION

It is well known that the reduction of aromatic nitro groups can give rise to toxic species, and that net nitro reduction by one-electron re ductases can usually be inhibited by oxygen. There has been much inter est in utilizing this biotransformation to activate drugs in hypoxic r egions of tumors, but no clinically useful compound has yet resulted. Nitroreductive activation of prodrugs by oxygen-insensitive (and oxyge n-sensitive) reductases is also of current interest because of new met hods for introducing specific nitroreductases into tumors (e.g., as an tibody-enzyme conjugates or by gene therapy). In most of the compounds investigated previously, cytotoxicity appears to be due to reactive n itroso or hydroxylamine reduction products arising from the nitro grou p itself. It is argued that there is greater scope for designing poten t and selective nitro compounds by using the nitro group as an electro nic switch to activate a latent reactive moiety elsewhere in the molec ule. Examples of this approach include the nitro(hetero)aromatic musta rds (e.g., SN 23816, NSC 646394) in which the nitro group controls the reactivity of a nitrogen mustard to which it is directly conjugated, and the nitro(hetero)aromatic methylquaternary (NMQ) mustards (e.g., S N 25341, NSC 658926) in which reduction of the nitro group triggers fr agmentation of the molecule to release a reactive aliphatic nitrogen m ustard. Many of these compounds show very high selectivity for hypoxic cells in culture. Some are also active against hypoxic cells in tumor s, and provide large tumor growth delays when combined with tumor bloo d flow inhibitors such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) . These prodrug designs also have potential for releasing effecters ot her than nitrogen mustards, which opens up many possibilities for use of nitro compounds as tumor-selective prodrugs.