Evaluation of DNA binding characteristics of some CC-1065 analogs.
The factors influencing the binding of CC-1065 to DNA were examined using racemic analogs with varying chain lengths. The ability of these agents to bind DNA appeared to be related to cytotoxic potency, however this did not appear to be a direct quantitative correlation. Two enantiomers of a bis-indole analog of CC-1065 were studied for DNA binding and cytotoxic activity. The agent with the same stereochemical configuration as CC-1065 was a potent cytotoxin, but its enantiomer was essentially inactive. Both enantiomers showed significant binding to DNA, but the biologically less active isomer showed less overall binding. In all cases, the agents preferred AT-rich DNA, and all bound to similar regions in DNA as evidenced by positions of drug-initiated thermal breaks in single end-labelled fragments of phi X 174RF DNA. The overall similarity in site specificity for binding of the structurally diverse agents suggests that much of the specificity observed in binding of the agent to DNA lies in the DNA itself. Thus, it may be difficult to change minor groove specificity for agents of this type simply by designing structures that can encompass guanine or cytosine residues. Other modifications, such as changing the specificity of the alkylating moiety, may be required to achieve this goal.
Swenson
D H
DH
Karkinos Biochem. Inc., Phoenix, AZ 85040.
Petzold
G L
GL
Williams
M G
MG
Li
L H
LH
Prairie
M D
MD
Krueger
W C
WC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004278:DNA, Superhelical / Q000187:drug effects; D000080890:Duocarmycins; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007933:Leucomycins / Q000494:pharmacology* / Q000633:toxicity; D007939:Leukemia L1210; D008623:Mercaptoethanol / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D010880:Piperidines; C054483:U 71184; D008623:Mercaptoethanol; C032727:piperidine; C018782:CC 1065; D004247:DNA