Double-strand cleavage of DNA by a monofunctional transition metal cleavage agent

A copper-based transition metal complex has been designed which performs double-stranded cleavage of DNA in a nonrandom fashion. The complex, ((2S, 8R)-5-amino-2,8-dibenzyl-5-methyl-3,7-diazanonanedioate)copper-(II), presents an ammonium group on one side of the metal equatorial coordination plane to the DNA backbone phosphate groups, while the aromatic phenylalanine-derived side chains are constrained to the opposite side of the coordination plane toward the DNA groove. This structure was designed to bind at locations where phosphate groups are in proximity to accessible hydrophobic regions of the DNA. We have estimated single-strand break to double-strand break ratios for DNA strand scission by this complex under a variety of activation conditions, and they are substantially lower than that predicted by statistical models for a random DNA linearization process. This means that more double-strand breaks are produced per single strand break than can be accounted for by random coincident single-strand breaks. We have also investigated the formation of abasic sites, and found that at least as many abasic sites can be cleaved to linear DNA as are linearized in the initial cleavage reaction. We interpret this to mean that the complex binds both at the intact DNA surface for strand scission, and binds at nicked sites on the DNA (where the charged end groups of the nick are likely to be proximate to the accessible hydrophobic interior) for reactivation and complementary strand scission. Insofar as double-strand cleavage may be more potent biologically than single-strand cleavage as a source of lethal DNA lesions, the recognition characteristics of this complex may aid in the design of chemotherapeutic agents.