of these compounds as DNA alkylating agents (see Section 2.4 of Chapter 5). The simplest such prodrug is the nitrophenyl mustard (11.9), but it shows only a modest hypoxic selectivity because, due to its low-reduction potential of about —515 mV, only a small amount of the drug is likely to be reduced. Accordingly, its 2,4-dinitro analogue (SN-23862), in which the electron-attracting properties of the second nitro group induce a higher-reduction potential, has a higher-hypoxic selectivity. Overall, this strategy is not very useful, because the presence of two or more electron-deficient groups onto the benzene ring of a nitrophenyl mustard to ensure a high enough reduction potential results in a low cytotoxicity even after reductive activation of part of these groups. This is also true for analogues based on heteroaromatic mustards such as 11.10.

11.9 sn-23862 11.10

Further problems associated with the presence of several nitro groups attached to the benzene ring of a nitrogen mustard are due to metabolic side reactions that contribute to its deactivation. For instance, the reductive metabolism of SN-23862

involves the predominant reduction of the nitro group ortho to the mustard moiety, which affords a mixture of hydroxylamino (11.11) and amino (11.12) reduction products. These metabolites undergo a fast intramolecular cyclization to tetrahydroquinoxaline derivatives 11.1312 where most antitumor activity has been lost (Fig. 11.13).

Another mechanism studied involves the generation of an active fragment after a bioreductive process. For instance, reduction of nitrobenzyl carbamates such as 11.14 to its hydroxylamino metabolite generates an electrophilic quino-neimine methide 11.15 together with amine R-NH2, though the reduction potential is too low and for this reason this bioreduction is inefficient (Fig. 11.14).

The same problem related to a too low value for the reduction potential has been shown in the bioreductive activation of the fluorouracil prodrug 11.16, which has been designed to generate the active drug by a ''through-space'' cyclization-extrusion process in the reduced metabolite 11.17 (Fig. 11.15).

2.2.4. Cobalt complexes

As already mentioned in Section 2.4 of Chapter 5, another strategy to design hypoxic-selective nitrogen mustards has been the complexation of both nitrogen atoms from bidentate mustards with transition metals such as cobalt. Complexes in the low-spin Co (III) oxidation state, such as SN-24771, are very stable and have appropriate reduction potential values to be reduced by cellular reductases. This reduction is competitively inhibited by oxygen, but under hypoxia the unstable high-spin Co (II) species resulting from reduction rapidly releases its ligands to

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