NITROBENZYL MUSTARD QUATERNARY-SALTS - A NEW CLASS OF HYPOXIA-SELECTIVE CYTOTOXINS CAPABLE OF RELEASING DIFFUSIBLE CYTOTOXINS ON BIOREDUCTION

Purpose: To explore the utility of a new class of compounds, nitrobenzyl mustard quaternary salts, as hypoxia-selective prodrugs of diffusible cytotoxins. Methods and Materials: The parent compound N,N-bis(2-chloroethyl)-N-methyl-N-(2-nitrobenzyl)ammonium chloride (SN 25246) was prepared by reaction of 2-nitrobenzyl chloride with N-methyldiethanolamine, and reaction of the resulting quaternary diol with thionyl chloride at room temperature. The rate of release of mechlorethamine from this compound in the presence of cells under aerobic and hypoxic conditions was determined by trapping with diethyldithiocarbamate. Cytotoxicity was assessed by clonogenic assay of stirred suspension cultures of EMT6 cells, and also in intact and dissociated EMT6 spheroids. In vivo activity was evaluated in mice bearing SC KHT tumors.