| Abstract
| - N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypicalmembers of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumoragents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carryan intrinsic higher concentration of “reducing” nucleophiles (e.g., thiols) capable of activating such derivatives(tunable N−O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studiesindicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activityapproaching or matching the activity of the free drug, yet remain essentially stable and unreactive to invitro DNA alkylation conditions (<0.1−0.01% free drug release) and pH 7.0 phosphate buffer, and exhibita robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrugin vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2),indicating that not only is the free drug effectively released from the inactive prodrug but also that theyoffer additional advantages related to a controlled or targeted release in vivo.
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