Are the Duocarmycin and CC-1065 DNA Alkylation Reactions Acid-Catalyzed? Solvolysis pH-Rate Profiles Suggest They Are Not.
A study of the solvolysis pH-rate profiles for two key reactive CC-1065/duocarmycin alkylation subunit analogues is detailed. Unlike the authentic alkylation subunits and N-BOC-CBI (4) which are too stable to establish complete solvolysis pH-rate profiles, the analogues N-BOC-CBQ (5) and N-BOC-CNA (6) are reactive throughout the pH range of 2-12. Moreover, they possess progressively diminished vinylogous amide conjugation resulting in a corresponding progressively increasing reactivity adopting and reflecting conformations analogous to that proposed for DNA-bound CC-1065. For both, the acid-catalyzed reaction was observed only at the lower pH of 2-5, and the uncatalyzed solvolysis reaction rate dominated at pH >/=6, indicating that the CC-1065 and duocarmycin DNA alkylation reaction observed at pH 7.4 need not be an acid-catalyzed reaction. The studies provide further strong evidence that catalysis for the DNA alkylation reaction (pH 7.4) is derived from a DNA binding-induced conformational change in the agents that disrupts the stabilizing alkylation subunit vinylogous amide conjugation activating the agents for nucleophilic attack independent of pH.
Boger
Dale L.
DL
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
Garbaccio
Robert M.
RM