Fv. Pamatong et al., DOUBLE-STRAND CLEAVAGE OF DNA BY A MONOFUNCTIONAL TRANSITION-METAL CLEAVAGE AGENT, Journal of the American Chemical Society, 118(23), 1996, pp. 5339-5345
A copper-based transition metal complex has been designed which perfor
ms double-stranded cleavage of DNA in a nonrandom fashion. The complex
, ((2S, benzyl-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 phenylalanin
e-derived side chains are constrained to the opposite side of the coor
dination plane toward the DNA groove. This structure was designed to b
ind 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 linea
rization process. This means that more double-strand breaks are produc
ed per single strand break than can be accounted for by random coincid
ent single-strand breaks. We have also investigated the formation of a
basic sites, and found that at least as many abasic sites can be cleav
ed to linear DNA as are linearized in the initial cleavage reaction. W
e 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 (wh
ere the charged end groups of the nick are likely to be proximate to t
he 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 le
sions, the recognition characteristics of this complex may aid in the
design of chemotherapeutic agents.