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O2 O2

FIGURE 5.10 Reduction of nitro and azo compounds.

Inactive Cl

FIGURE 5.11 Aromatic nitrogen mustard prodrugs for selective activation in hypoxic tissues.

Inactive Cl

FIGURE 5.11 Aromatic nitrogen mustard prodrugs for selective activation in hypoxic tissues.

further details on the use of Co (III) complexes in hypoxia-based strategies for tumor-specific prodrug activation.

More complex approaches are based on the distal activation concept, where the reductive process uncovers a nucleophilic or basic center that then triggers the liberation of the alkylating agent by reaction with a distant part of the molecule. Thus, the phosphoramide mustard prodrug 5.18 is activated by reduction of its nitro group to amino, which increases the basicity of the quinoline nitrogen sufficiently to allow the elimination reaction depicted in Fig. 5.13.

A related example is based on the reduction of a quinone system, which uncovers two nucleophilic hydroxyl groups, as shown in Fig. 5.14 for the case of the melphalan prodrug 5.19.18 The conformation needed for the reaction that liberates the active drug is favored by the presence of the methyl groups because it is less sterically compressed than alternative conformations (Thorpe-Ingold effect).

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