Establishing the Parabolic Relationship between Reactivity and Activity for Derivatives and Analogues of the Duocarmycin and CC-1065 Alkylation Subunits

The preparation of a novel series of N-aryl CBI derivatives is detailed in which an aryl para substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue (ρ = 0.17). The derivatives were found to be exceptionally stable and to exhibit a well-defined relationship between reactivity and cytotoxic potency. When combined with the results of an extensive series of N-acyl CBI analogues and derivatives assembled over the past 15 years, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency.