plasma, but the disulfide is reduced by glutathione transferase in the kidney, liberating the thiol that inactivates acrolein through a conjugate addition, giving compounds such as 5.17 for the case of mesna (Fig. 5.9).

Another biochemical difference between some tumors and normal tissues is based on their different reducing capacities. The inner regions of solid tumors have little vascularization and therefore their oxygen content is low (for a more detailed treatment of hypoxia-based strategies for tumor-specific prodrug activation, see Section 2.2 of Chapter 11). Because molecular oxygen reverts some of the reactions of reductive metabolism, the latter is enhanced in hypoxic tissues. Some of these reactions are nitro and azo reduction, which are multistep processes where oxygen reverts the first equilibrium (Fig. 5.10).

On this basis, some aromatic nitrogen mustard prodrugs bearing nitro or azo groups have been designed to be activated in these hypoxic environments. In the simplest of them, the presence of these electron-withdrawing groups in the p-position with respect to the nitrogen atom prevents cyclization to an

10 Ways To Fight Off Cancer

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