| Abstract
| - The antitumor antibiotics FR66979 (1), FR900482(2), and FK973 (3) are similar in structure andbiologicalactivity to the DNA cross-linking antitumor antibiotic mitomycin C(4). The cytotoxic effects of1−3 have beenproposed to result from sequential bioreductive cleavage of the N−Obond and condensation of the thus-exposedamine and ketone functions to yield an indole (e.g., 9)which is structurally analogous to the mitosene nucleus ofreductively activated mitomycins. We report herein evidencesubstantiating this proposal based upon study of thereductive activation chemistry of 1 and 2 usingthiols and iron(II) in the absence and presence of DNA.Prolongedexposure of reductively activated 1 to sodium borohydrideafforded the dihydroindole 11, presumably throughtrappingof the iminium ion precursor (16). Kineticsmeasurements strongly implicate a relatively long-lived precursor totheiminium ion, which accumulates following iron(II)-catalyzedthiol-promoted reduction of 1, proposed herein tobeone or both of the isomeric aminals 12. Underappropriate conditions, some step or steps between thisintermediateand the iminium ion are shown to be rate limiting in DNA cross-linking,in production of the dihydroindole byborohydride trapping, and in the decay of the intermediate(s)competent to produce those same products. Thesestudies clearly demonstrate the strong similarities in the cascade ofreactions which follow reductive activation ofFR66979 (1) [and presumably by extension FR900482(2) and FK973 (3)] and themitomycins.
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