Molecular recognition effects in metal complex mediated double-strand cleavage of DNA: Reactivity and binding studies with model substrates

Double-strand breaks in duplex DNA are thought to be significant sources of cell lethality because they appear to be less readily repaired by DNA repair mechanisms. We recently described the design and cleavage chemistry of ((2S,8R)-5-amino-2,8-dibenzyl-5-methyl-3,7-diazanonanedioato)copper(II) (1), which effects nonrandom double-strand cleavage of duplex DNA. After DNA nicking by generation of hydroxyl radicals, the key step in this process appears to occur through recognition by the metal complex of the nicked-abasic site on duplex DNA, followed by delivery of OH. to cleave at the opposing strand, forming a double-strand lesion. Tkrough the use of model nucleic acid substrates and comparison to DNA scission chemistry, we have investigated the electrostatic and hydrophobic contributions to DNA binding by complex 1. We have complemented these reactivity studies with studies on the binding of 1 to a model nucleic acid substrate, using H-2 NMR spectroscopy with deuterated 1 and HDO T-1 relaxation enhancement methods to study the binding of 1 to nucleotide substrates. With these methods, we have estimated that the association constant for the 1(+).5'-AMP(2-) complex is similar to 16 M-1 and that the binding interaction involves both electrostatic and aromatic stacking interactions between the nucleic acid base and the pendant aromatic side chains of 1.