CYCLOPROPAMITOSENES, NOVEL BIOREDUCTIVE ANTICANCER AGENTS - SYNTHESIS, ELECTROCHEMISTRY, AND BIOLOGICAL-ACTIVITY OF 7-SUBSTITUTED CYCLOPROPAMITOSENES AND RELATED INDOLEQUINONES

The synthesis of the indolequinones 8 and 9 starting from methyl 4-(be nzyloxy)-5-methoxyindole-2-carboxylate (10) is described. The methoxy group in the indolequinones 1, 2, 4, 5, and 7-9 can be displaced by va rious nitrogen nucleophiles (ammonia, 2-methoxyethylamine, aziridine, 2-methylaziridine, pyrrolidine) in 22-88% yield. The resulting amino-s ubstituted quinones, together with their methoxy precursors, were stud ied by cyclic voltammetry to determine their reduction potentials, whi ch, in DMF solution, lie in the range -1.355 to -1.597 V (vs ferrocene ). The cytotoxicity of the compounds towards aerobic and hypoxic mamma lian cells was also determined; in general, under aerobic conditions, the cyclopropamitosenes are more toxic than the corresponding pyrrolo[ 1,2-alpha]indolequinones, which are in turn more toxic than the simple 1,2-dimethylindolequinones, with many of the compounds in each series showing greater toxicity toward hypoxic cells.