CC-1065 functional analogues possessing different electron-withdrawing substituents and leaving groups: synthesis, kinetics, and sequence specificity of reaction with DNA and biological evaluation.
Antitumor agent CC-1065 functional analogues possessing different electron-withdrawing substituents and leaving groups have been synthesized. The extent and the relative rates of DNA cleavage following alkylation by these CPI structures and thermal treatment were determined independently by an ethidium binding assay and by agarose gel electrophoresis experiments. The anticipated preferential covalent binding to adenine sites within the minor groove was confirmed by sequencing determination of selected agents on high-resolution gels. Certain of the synthetic agents, unlike CC-1065, also bind covalently to G sites with weaker intensity. The cytotoxicities of these compounds were also determined against KB cells in vitro. Compounds bearing a bromo or nitro group in the benzene ring and a methylsulfonyl as a leaving group are 10 and 5 times more potent than their unsubstituted counterparts, respectively. Compounds bearing a methylsulfonyl as a leaving group are more potent than those bearing a chlorine.
Wang
Y
Y
Department of Chemistry, University of Alberta, Edmonton, Canada.
Gupta
R
R
Huang
L
L
Lown
J W
JW
D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D015246:Deoxyribonuclease EcoRI / Q000378:metabolism; D000080890:Duocarmycins; D006358:Hot Temperature; D007211:Indoles; D007700:Kinetics; D007933:Leucomycins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; D004247:DNA; D015246:Deoxyribonuclease EcoRI