Some reactions and properties of nitro radical-anions important in biology and medicine.

Abstract

Nitroaromatic compounds, ArNO2 have widespread actual or potential use in medicine and cancer therapy. There is direct proof that free-radical metabolites are involved in many applications, and an appreciation of the conceptual basis for their therapeutic differential; however, an understanding of the detailed mechanisms involved is lacking. Redox properties control most biological responses of nitro compounds, and the characteristics of the one-electron couple: ArNO2/ArNO2- are detailed. The "futile metabolism" of nitroaryl compounds characteristic of most aerobic nitroreductase systems reflects competition between natural radical-decay pathways and a one-electron transfer reaction to yield superoxide ion, O2-. Prototropic properties control the rate of radical decay, and redox properties control the rate of electron transfer to O2 or other acceptors. There are clear parallels in the chemistry of ArNO2- and O2-. While nitro radicals have frequently been invoked as damaging species, they are very unreactive (except as simple reductants). It seems likely that reductive metabolism of nitroaryl compounds, although generally involving nitro radical-anions as obligate intermediates (and this is required for therapeutic selectivity towards anaerobes), results in biological damage via reductive metabolites of higher reduction order than the one-electron product.

Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

“…Previous studies with benznidazole and other 2-nitroimidazoles have shown that the dihydro-dihydroxy reduction product can readily form adducts with guanosine, either directly or via released glyoxal (44,47) (Fig. 6A).…”

“…In this system, a series of 2-electron reductions results in the formation of the hydroxylamine derivative without the formation of the nitro anion radical. Although the aerobic reduction of nitroimidazoles by type I nitroreductases is thermodynamically unfavorable-the reduction potential (E 0 ) of the FMN cofactor at pH 7.0 is higher (E 0 between Ϫ90 and Ϫ290 mV) than that of many of the substrates (e.g., E 0 values for 5-nitroimidazoles range between Ϫ400 and Ϫ510 mV) (29,47)-this system still represents a major activation mechanism of this compound class by microaerophilic microbes such as Helicobacter species (8).…”

Nitroimidazoles with a halogen-containing side-chain

“…28 The NO 2 -group undergoes reduction steps to give finally the amine (Scheme 6), the degree of reduction being determined enzymatically. 29 The stability of the initially formed radical anion also depends on pH, which decreases below physiological values during radiation with a corresponding increase in DNA Insert Table 2 somewhere here…”

Redox cycling of radical anion metabolites of toxic chemicals and drugs and the Marcus theory of electron transfer.

“…Wardman (27) has proposed that the reduction potential, E' (1-electron potential in water at pH 7), of nitro aromatic compounds is the most appropriate index of the redox properties of nitroaromatic compounds because it is the thermodynamic parameter that characterizes the relative ease of reduction of these compounds (27).…”

“…Since AG* is defined by AE' for a one-electron transfer reaction, if the individual reduction potentials are known, then the rate constant k, as well as the equilibrium constant K1 can be predicted. Over small ranges in AE', log k, is proportional to El (27).…”