SYNTHESIS AND EVALUATION OF IMIDAZOLYL DISULFIDES FOR SELECTIVE CYTOTOXICITY TO HYPOXIC EMT6 TUMOR-CELLS INVITRO

Two series of disulfides were synthesized and evaluated in vitro for selective hypoxic tumor cell cytotoxicity using EMT6 cells. While the series of alkyl 5-nitrobenzimidazolyl disulfides displayed no selectivity, two alkyl imidazolyl disulfides, devoid of a nitro function, showed preferential toxicity to EMT6 cells treated under hypoxic conditions. Select agents of the alkyl imidazolyl series were found to deplete cellular glutathione (GSH) while the corresponding alkyl nitrobenzimidazolyl derivatives did not. One disulfide displaying selective hypoxic cell toxicity, n-butyl 2-imidazolyl disulfide, 10, caused significantly greater depletion of GSH under aerobic conditions. Removal of cellular GSH with buthionine sulfoximine (BSO) prior to exposure to 10 caused an increase in its toxicity and a loss of any differential between aerobic and hypoxic conditions. It is speculated that the diminished aerobic vs hypoxic toxicity of the agent toward EMT6 cells is due to a greater ability of 10 to interact with GSH under aerobic conditions as reflected by the greater GSH depletion.