ABSTRACT
Four 2-alkysulfonyloxy-3-hydroxy-1,4-naphthoquinone derivatives, VH(1-4), have been synthesized as a novel class of bioreductive alkylating agents and tested as hypoxic cytotoxins, radiosensitizers, and chemosensitizers of V79 cells. In this series, the naphthoquinone is the bioreductive moiety while the sulfonyloxy group, as a good leaving group, could lead to alkylations of nucleophilic substrates in the cells. All VH-compounds are moderately selective cytotoxins of V79 cells with a differential aerobic-hypoxic toxicity of approximately 2, i.e. ratio of drug concentrations to give 50% killing for aerobic versus hypoxic cells. All derivatives are radiosensitizers of hypoxic V79 cells but only VH-3 can give a sensitization enhancement ratio of 2.05 at a nontoxic concentration. Finally, all VH-derivatives are good chemosensitizers of V79 cells to the aerobic toxicity of melphalan, either under hypoxic preincubation without melphalan or under aerobic coincubation with melphalan. The dose modification factors were approximately 2, at low, non-toxic concentrations.
