Propargylic sulfones possessing a 2-nitroimidazole function: novel hypoxic-cell radiosensitizers with intracellular non-protein thiol depletion ability

Abstract

Propargylic sulfones containing a 2-nitroimidazole function have been synthesized to evaluate their hypoxic-cell radiosensitizing activity toward EMT6/KU tumor cells and intracellular nonprotein thiol (NPSH) depletion reactivity. Propargylic sulfones ( 1a – c ) containing a 2-nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intracellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward hypoxic EMT6/KU tumor cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent hypoxic-cell radiosensitization by propargylic sulfones possessing a 2-nitroimidazole function in biological systems.