INDOLEQUINONE ANTITUMOR AGENTS - CORRELATION BETWEEN QUINONE STRUCTURE, RATE OF METABOLISM BY RECOMBINANT HUMAN NAD(P)H-QUINONE OXIDOREDUCTASE, AND IN-VITRO CYTOTOXICITY

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H: quinone oxidoreductase (NQO1) w ere studied. Thus 5-methoxyindolequinones were prepared by the Nenitze scu reaction, followed by functional group interconversions. The metho xy group was subsequently displaced by amine nucleophiles to give a se ries of amine-substituted quinones. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, whereas thos e with amine groups at the 5-position were poor substrates. Compounds with a leaving group at the 3-indolyl methyl position generally inacti vated the enzyme. The toxicity toward non-small-cell lung cancer cells with either high NQO1 activity (H460) or no detectable activity (H596 ) was also studied in representative quinones. Compounds which were go od substrates for NQO1 showed the highest selectivity between the two cell lines.