DNA microstructural requirements for neocarzinostatin chromophore-induced direct strand cleavage.
The microstructural requirements for optimal interaction of neocarzinostatin chromophore (NCS-C) with DNA have been investigated using a series of hexadeoxyribonucleotides with modified bases such as O6-methyl G (MeG), I, 5-methyl C (MeC), U, or 5-Bromo U (BrU) at specific sites in its preferred trinucleotide 5'GNaNb3':5'Na,Nb,C3' (Na = A, C, or T). Results show that MeG:C and G:MeC in place of G:C improve direct strand cleavage at the target Nb (Nb = T greater than A much greater than C greater than G), whereas MeC:G and C:MeG in place of Na:Nb, hinder cleavage. The optimal base target at Nb appears to be determined by its ability to form T:A type base pairing instead of C:G type. The observed differences in DNA strand cleavage patterns can be rationalized by induced changes in target site structure and are compatible with a model for NCS-C:DNA interaction in which the naphthoate moiety intercalates between 5'GNa3', and the activated tetrahydro-s-indacene, lying in the minor groove, abstracts a hydrogen atom from C-5' of Nb.
Lee
S H
SH
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Thivierge
J O
JO
Goldberg
I H
IH
D000903:Antibiotics, Antineoplastic / Q000031:analogs & derivatives / Q000494:pharmacology; D001482:Base Composition; D001483:Base Sequence; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000187:drug effects / Q000648:ultrastructure*; D053281:Enediynes; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D009353:Zinostatin / Q000031:analogs & derivatives / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D009838:Oligodeoxyribonucleotides; C032372:neocarzinostatin chromophore; D004247:DNA; D009353:Zinostatin