Nitroarylmethyl quaternary ammonium nitrogen mustards are bioreductive drugs designed to release mechlorethamine, when reduced metabolically, via fragmentation of the initial nitro radical anion to a benzylic-type radical. This proposed mechanism (termed Type I) is analogous to the well-known reductive fragmentation of 2-nitrobenzyl halides. The lead nitroarylmethyl quaternary mustard SN 25246 (NSC 656581), which contains a 2-nitrobenzyl electron acceptor, was shown previously to release mechlorethamine in hypoxic cell cultures and to be a highly selective hypoxic cytotoxin. In the present work the mechanism of reductive release of mechlorethamine from nitroarylmethyl quaternary prodrugs was investigated by steady-state radiolysis with product analysis by high-performance liquid chromatography. SN 25246 releases mechlorethamine in high yield upon reduction, but several reducing equivalents are required (Type II mechanisms). Investigation of other nitroarylmethyl units identified two heterocyclic analogues, the 1-methyl-4-nitro-5-imidazolyl derivative SN 25341 and the 1-methyl-5-nitro-2-pyrrolyl derivative SN 26581, which have a reduction stoichiometry of about one reducing equivalent and which release mechlorethamine efficiently. The other products from reduction of SN 25341 are also consistent with Type I fragmentation, via intramolecular electron transfer, to give the$1\text{-methyl-}4\text{-nitroimidazole-}5\text{-}{\rm CH}_{2}{}^{\bullet}$ radical. The sensitivity of the 4-nitroimidazole and 5-nitropyrrole nitroarylmethyl quaternary mustards to Type I reductive fragmentation suggests that these electron acceptor units may be well suited to development of prodrugs which release tertiary amine effectors after metabolic or radiolytic reduction in hypoxic regions of tumors.

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