Sequence-specific, strand-selective, and directional binding of neocarzinostatin chromophore to oligodeoxyribonucleotides.

The sequence-specific interaction of neocarzinostatin chromophore (NCS-C) has been evaluated with a series of synthetic oligodeoxyribonucleotides of defined sequences containing the most preferred nucleotide cleavage site, T or A, or both. NCS-C preferentially cleaves T or A residues in the sequence GN1N2, where N2 is T or A. Greater cleavage occurs on the strand enriched with G residues, provided that they are adjacent to other G residues, but not at N1. These results are compatible with a model for drug binding in which the naphthoate moiety of NCS-C preferentially intercalates at GN1. This is accompanied by electrostatic binding interaction provided by the positively charged amino sugar moiety so as to place the reactive bicyclo[7.3.0]dodecadienediyne epoxide moiety in an appropriate orientation in the minor groove enabling, upon thiol activation, attack at C-5' of T or A. At certain sequences, such as GCT.AGC, a similar binding mode is also able to generate a basic lesions at the C residue on the opposite strand, forming a bistranded lesion. Although the reactions with glutathione generally show the same strand selectivity and sequence specificity as those with dithiothreitol, the former is usually more efficient than the latter.