2.2.3. Aromatic nitro derivatives

Nitroaromatic compounds are reduced by several nitroreductases, which are flavoprotein enzymes that catalyze the stepwise addition of up to six electrons, though the major metabolite is normally the hydroxylamine formed by addition of four electrons. In nitroaromatic compounds with suitable reduction potentials (around —330 to —450 mV), the first radical anion formed by one-electron addition can be scavenged efficiently by molecular oxygen, and consequently its formation is restricted to hypoxic cells. Compounds with reduction potentials outside this range are less useful, either because they are too easily reduced and therefore show less selectivity for hypoxic tissues (reduction potentials higher than —330 mV) or because they are too difficult to activate (reduction potentials below —450 mV).

The main nitroaromatic compounds used in cancer chemotherapy are nitroi-midazoles. These compounds were introduced as radiosensitizers (see Section 11 of Chapter 4), but it was later shown that they were able to induce cell death in hypoxic environments in the absence of radiation. This cytotoxic activity is mainly due to the nitro radical anion 11.6 and hydroxylamine (11.8) metabolites. Thus, 11.6 or its protonated derivative 11.7 can oxidize DNA chains (see also Section 11 of Chapter 4), while the O-acetyl derivative of hydroxylamine 11.8 may give covalent DNA adducts (Fig. 11.11).11

Although the observation of cytotoxic activity in the absence of radiation normally requires concentrations of the nitro derivative that are too high to be found in clinical situations, the presence of two alkylating moieties can lead to improved activity. For instance, RSU-1069 behaves as a DNA monoalkylator in normal tissues and as a bisalkylator under hypoxic environments, where it is 50-100 times more cytotoxic (Fig. 11.12). Unfortunately, clinical studies of this compound showed a high-intestinal toxicity that prevented its further development.

Nitracrine is another nitro derivative with selective cytotoxicity in hypoxic cell cultures, and it has been shown that besides its DNA intercalating properties it is able to alkylate DNA following reduction by thiols or enzymes, though the nature of the electrophilic metabolites generated in the bioreductive process is still debated. Unfortunately, the hypoxia selectivity has not been observed in solid tumors, probably because the high-reduction potential (-303 mV) and the tight DNA binding of this compound slows its diffusion into hypoxic areas.

Since the alkylating reactivity of aromatic mustards is greatly determined by the electron density in the mustard nitrogen, enzymatic reduction of a nitro group on the aromatic ring to a hydroxylamine derivative can result in a higher potency


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