Double-Strand Cleavage of DNA by a Monofunctional Transition Metal Cleavage Agent

Abstract

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.

Efficient DNA Cleavage Induced by Copper(II) Complexes of Hydrolysis Derivatives of 2,4,6‐Tri(2‐pyridyl)‐1,3,5‐triazine in the Presence of Reducing Agents

“…In general, two mechanisms can be proposed for Cu II complexes that mediate oxidative DNA cleavage, one involving hydroxyl radicals and another involving metal-oxido species. Bocarsly et al [49,50,53] have suggested that hydroxyl radicals are generated by a variety of chemical and physical processes. Transition-metal-mediated hydroxyl radical production is known to occur by a number of routes; two well-known pathways are the Fenton and the HaberWeiss mechanism.…”

Efficient DNA Cleavage by Acridine Conjugates of Mono- and Dinuclear Cu(II) Complexes

“…Characterization of the intermediates was based on Mass data. 1 H and 13 C NMR spectra were complex since there existed several conformers of N-Boc-protected tacn moieties. Figure 2 showed UV/Vis absorption titration spectrum of the Cu 2 L3 and CuL4 complexes with calf-thymus (CT) DNA at pH 7 and 25 o C. In the absence of DNA, 9-amino-acridine showed its maximum absorbance at 382 nm, 399 nm, and 420 nm and both Cu 2 L3 and CuL4 complexes at 392 nm, 411 nm, and 433 nm.…”

Synthesis, X‐ray Crystal Structures, DNA Binding and Nuclease Activities of Two Novel 1,2,4‐Triazole‐Based CuII Complexes

“…Supercoiled plasmid DNA values were corrected by a factor of 1.3, based on the average literature estimate of lowered binding of ethidium. [64] Cleavage mechanistic investigation of pBR322 DNA was done using different reagents such as DMSO, EtOH, NaN 3 , -histidine, SOD, KI, SYBR Green, methyl green and EDTA added to pBR322 DNA prior to the addition of complexes.…”