AreOrtho-substituted 4-nitroimidazoles a New Generation of Radiation-induced Arylating Agents?

Some Reactions and Properties of Nitro Radical-Anions Important in Biology and Medicine

“…Similar behavior is seen with 5-and 8-(halomethyl)-1-nitronaphthalenes and with (4-nitrobenzyl)tosyl derivatives (92). However, 4-halonitrobenzene radical-anions decay via second-order kinetics (with k for halide elimination < 1/sec) (93), and the radical-ion of 4-chloro-1-methyl-5-nitroimidazole is similarly long-lived (81). In spite of the apparently normal disproportionation behavior of the latter radical, significant yields of halide ion are eventually produced (at times > 1 sec) following one-electron reduction of this ring-halogenated nitroimidazole (81) and analogs (94).…”

“…Lifetimes of nitroimidazole radicals are many seconds at high pH (4,21,24,81), similar to the behavior of radicals from nitrobenzene and derivatives (18,19,85,86). A report (23) that the second-order rate constant for the decay of the 5-nitrofuroic acid radical anion remained essentially unchanged (2k = 2.2 x 109 dm3/ mole-sec) from pH 10.5 to 3.3 is completely inconsistent in both magnitude and pH-independence with numerous with Ea all in the range 30-39 kJ/mole; the algorithms for the temperature dependences of k2 for metronidazole and misonidazole have been reported (4,21).…”

“…A typical example in the important 2-nitro-1-imidazolylalkylamine series has been discussed (59). More dramatic shifts in pKa between ground state and one-electron adduct are found with the protonation of the unsubstituted (N-3) imidazolyl nitrogen in some simple N-1 alkyl/alkanol substituted 2-, 4-and 5-nitroimidazoles, where the increase in pKa upon electron addition is around 6.2, 5.5, and 3.6 units, respectively (24,81). ESR studies have characterized the dissociation of acidic ring N-H protons in other nitroaryl radical-anions lacking carbon substitution at nitrogen (80,82).…”

Cytotoxic properties of a 4-nitroimidazole (NSC 38087): A radiosensitizer of hypoxic cells in vitro

“…In the presence of 02, reduction of RNO2 is inhibited by electron transfer from RNO2 to 02 (Mason & Holtzman, 1975b;Wardman & Clarke, 1976). Recently it was proposed that 5-chloro-1 -methyl-4-nitroimidazole and related 5-substituted 4-nitroimidazoles, such as those reported here, would be more toxic towards hypoxic cells than would be expected on an electron-affinitv basis (Clarke & Wardman, 1980). These authors proposed that this could be due to initial formation of RNO2 followed by dissociative electron attachment with the resulting formation of a free radical or other species, which would be toxic.…”

“…These authors proposed that this could be due to initial formation of RNO2 followed by dissociative electron attachment with the resulting formation of a free radical or other species, which would be toxic. This scheme would be inhibited in the presence of 02 (Clarke & Wardman, 1980 At present there is no explanation for the differential toxicity of these compounds to aerobic cells, nor for their greater toxicity (in both air and N2) than would be predicted from their electron affinities (Adams et al, 1979b(Adams et al, , 1980b. However, it is known that related compounds such as Imuran (azathioprine, 6-(1 -methyl-4-nitro-5-imidazolyl) thiopurine) are cleaved rapidly in vivo to 6-mercaptopurine and 1-methyl-4-nitro-5-thiolimidazole (Bresnick, 1959;Elion, 1967).…”