CBI DERIVATIVES SUBJECT TO REDUCTIVE ACTIVATION

摘要

A unique class of N-acyl O-amino phenolprodrugs of CBI-TMI and CBI-indole2 were synthesizedand shown to be prodrugs, subject to reductive activationby nucleophilic cleavage of a weak N-O bond, effectivelyreleasing the free drug in functional cellular assays forcytotoxic activity approaching or matching the activity ofthe free drug, yet remain essentially stable to ex vivo DNAalkylation conditions. Most impressively, assessment of thein vivo antitumor activity of a representative O- (acylamino)prodrug, 8, indicate that they approach the potency andexceed the efficacy of the free drug itself (CBI-indole2),indicating that the inactive prodrugs not only effectivelyrelease the free drug in vivo, but that they offer additionaladvantages related to a controlled or targeted release in vivo.