REDUCTION OF NITROARYLMETHYL QUATERNARY AMMONIUM PRODRUGS OF MECHLORETHAMINE BY RADIATION

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-t ype radical. This proposed mechanism (termed Type I) is analogous to t he well-known reductive fragmentation of 2-nitrobenzyl halides. The le ad nitroarylmethyl quaternary mustard SN 25246 (NSC 656581), which con tains a 2-nitrobenzyl electron acceptor, was shown previously to relea se mechlorethamine in hypoxic cell cultures and to be a highly selecti ve hypoxic cytotoxin. In the present work the mechanism of reductive r elease 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 req uired (Type II mechanisms). Investigation of other nitroarylmethyl uni ts identified two heterocyclic analogues, the 1-methyl-4-nitro-5-imida zolyl derivative SN 25341 and the 1-methyl-5-nitro-2-pyrrolyl derivati ve SN 26581, which have a reduction stoichiometry of about one reducin g equivalent and which release mechlorethamine efficiently. The other products from reduction of SN 25341 are also consistent with Type I fr agmentation, via intramolecular electron transfer, to give the 1-methy l-4-nitroimidazole-5-CH2. radical. The sensitivity of the 4-nitroimida zole and 5-nitropyrrole nitroarylmethyl quaternary mustards to Type I reductive fragmentation suggests that these electron acceptor units ma y be well suited to development of prodrugs which release tertiary ami ne effecters after metabolic or radiolytic reduction in hypoxic region s of tumors. (C) 1998 by Radiation Research Society.