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

摘要

CC-1065 (1), the duocarmycins (2-3), and yatakemycin (4) are the parent members of a class of potent antitumor antibiotics that derive their properties through a sequence-selective DNA alkylation (Figure 1). An extensive series of studies have characterized their structural features responsible for the DNA alkylation reaction and have established fundamental relationships between structure and activity. Among the most important of these relationships is a direct correlation between chemical stability and biological potency (cytotoxic activity). To date, this relationship covered a wide range of modified alkylation subunits with properties extending over a 10~6-fold range in both reactivities and activities. Restricted to derivatives that possess sufficient reactivity to alkylate DNA, this relationship has been interpreted to reflect the ability of the chemically more stable derivatives to more effectively reach their biological target (DNA).