Alkylation of guanine and cytosine in DNA by bizelesin. Evidence for a covalent immobilization leading to a proximity-driven alkylation of normally unreactive bases by a (+)-CC-1065 cross-linking compound.
Bizelesin, an intrahelical DNA-DNA interstrand cross-linker related to (+)-CC-1065, has been shown to alkylate DNA through guanine in restriction enzyme sequences in which there is a suitably positioned adenine contained in a highly reactive monoalkylation sequence on the opposite strand. Oligomers containing the sequence 5'-TTTTTN*, in which "N" was either G, C, or T, were synthesized to evaluate the cross-linking potential of bizelesin at nonadenine bases. Kinetic analysis of monoalkylation and cross-linking events demonstrates that it is the reaction at "N" (guanine or cytosine) that results in the cross-link which is the slow step. On the basis of this analysis and the normal unreactivity of guanine and cytosine to alkylation by the cyclopropapyrroloindole alkylating moiety of (+)-CC-1065, we propose that the molecular mechanism for this type of cross-linking reaction most likely involves a covalent immobilization of the second alkylating arm, resulting in a "proximity-driven" reaction.
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Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin 78712.
Park
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Hurley
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D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001482:Base Composition / Q000187:drug effects; D001483:Base Sequence; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D003596:Cytosine / Q000378:metabolism*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D000080890:Duocarmycins; D006147:Guanine / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D007933:Leucomycins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000138:chemical synthesis; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D009841:Oligonucleotides; D006147:Guanine; C018782:CC 1065; D003596:Cytosine; D014508:Urea; D004247:DNA; C072257:bizelesin