Catalysis of the CC-1065 and duocarmycin DNA alkylation reaction: DNA binding induced conformational change in the agent results in activation.
A number of indirect observations are summarized that suggest the rate acceleration for the CC-1065 and duocarmycin. DNA alkylation reaction is derived in part from a DNA binding-induced conformational change in the agents which substantially increases their inherent reactivity. This ground-state destabilization of the agent, which we suggest results from a binding-induced twist in the linking N2 amide and requires a rigid extended N2 amide substituent, disrupts the vinylogous amide stabilization and activates the agents for DNA alkylation.
Boger
D L
DL
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Garbaccio
R M
RM
D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D013237:Stereoisomerism
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; D004247:DNA