Factors Influencing the DNA Nuclease Activity of Iron, Cobalt, Nickel, and Copper Chelates

Abstract

A library of complexes that included iron, cobalt, nickel, and copper chelates of cyclam, cyclen, DOTA, DTPA, EDTA, tripeptide GGH, tetrapeptide KGHK, NTA, and TACN was evaluated for DNA nuclease activity, ascorbate consumption, superoxide and hydroxyl radical generation, and reduction potential under physiologically relevant conditions. Plasmid DNA cleavage rates demonstrated by combinations of each complex and biological coreactants were quantified by gel electrophoresis, yielding second-order rate constants for DNAsupercoiled to DNAnicked conversion up to 2.5 ×106 M-1min-1, and for DNAnicked to DNAlinear up to 7 ×105 M-1min-1. Relative rates of radical generation and characterization of radical species were determined by reaction with the fluorescent radical probe TEMPO-9-AC and rhodamine B. Ascorbate turnover rate constants ranging from 9.1×10-3 to 8.2 min-1 were determined, although many complexes demonstrated no measureable activity. Inhibition and Freifelder-Trumbo analysis of DNA cleavage supported concerted cleavage of dsDNA by a metal associated ROS in the case of Cu2+(aq), Cu-KGHK, Co-KGHK, and Cu-NTA and stepwise cleavage for Fe2+(aq), Cu-cyclam, Cu-cyclen, Co-cyclen, Cu-EDTA, Ni-EDTA, Co-EDTA, Cu-GGH, and Co-NTA. Reduction potentials varied over the range from -362 mV to +1111 mV versus NHE, and complexes demonstrated optimal catalytic activity in the range of the physiological redox coreactants ascorbate and peroxide (-66 to +380 mV).

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

“…Iron in its ferrous form and in an aqueous environment, can induce nonenzymatic strand cleavage and alkali-labile lesions (107,240). Iron can incorporate into DNA and bind to it, possibly more so in the ferrous than ferric form (232,263), although other studies suggest that the ferric form exerts the major stereochemical effect (6).…”

A solid-phase CuAAC strategy for the synthesis of PNA containing nucleobase surrogates

“…The to metal-free levels, but at high concentrations of Ni 2+ and EDTA (320 μM) degradation of the PNA hairpin may have occurred because an erosion of the Tm was observed (see Supplemental Materials). DNA degradation has been described for Ni 2+ ·EDTA complexes 27 and it is conceivable that the implied metal chelate reactive oxygen species responsible for this could damage the PNA oligomer.…”

The reactivity of macrocyclic Fe(II) paraCEST MRI contrast agents towards biologically relevant anions, cations, oxygen or peroxide

“…Dissociation of the complex can lead to potentially toxic conditions due to the free ligand or free metal ion. This is especially true for Fe(II) complexes because free Fe(II) can generate reactive oxygen species in the presence of oxygen, superoxide or peroxide [16][17][18]. However, the reactivity can be reduced by adjusting the reduction potential of the metal center through synthetic variation of pendent groups and by coordinatively saturating the Fe(II) center.…”

“…However, the reactivity can be reduced by adjusting the reduction potential of the metal center through synthetic variation of pendent groups and by coordinatively saturating the Fe(II) center. For example, multiple turnover redox cycles in the presence of ascorbate as reductant and oxygen or peroxide as oxidants are greatest for complexes with reduction potentials in the range of + 380 mV to −66 mV [16].…”