Ternary nickel(II) complexes as hydrolytic DNA-cleavage agents.

A series of small model complexes made from Ni(II) and the ligands ethylenediamine (en), histamine (hist), and histidylleucine (HisLeu) were prepared and studied as potential hydrolytic DNA-cleavage agents. The stability constants and species-distribution curves for these complexes were determined as a function of pH. The 1 : 1 : 1 ternary complexes [Ni(II)(en)(HisLeu)] (1) and [Ni(II)(hist)(HisLeu)] (2) were the only major species present at the physiologically relevant pH of 6-7, as further corroborated by ESI-MS analysis. The complex geometries of 1 and 2 were analyzed by UV/VIS experiments and molecular dynamics (MD) simulations. Both ternary complexes were found to intercalate with DNA, as shown by UV/VIS, thermal-denaturation, and fluorescence-titration studies with ethidium bromide (EB). The intrinsic binding constants (K(b)) for the bound complexes 1DNA and 2DNA were determined as 150 and 290, resp. Gel-electrophoresis experiments revealed that 1 and 2 cleave supercoiled (type-I) to nicked-circular (type-II) DNA at physiological pH, with rate constants of 0.64 and 0.75 h(-1), resp. A tentative mechanism for this hydrolytic cleavage is proposed.

Ternary zinc(II)-dipeptide complexes for the hydrolytic cleavage of DNA at physiological pH.

A series of Zn(II) complexes with cysteinylglycine (CysGly) and histidylserine (HisSer), and of CysGly and histidylphenylalanine (HisPhe) were investigated. Complex stabilities were determined potentiometrically, and binding geometries were probed by means of 1H-NMR spectroscopy, using Co(II) instead of Zn(II) as a spectroscopic marker. The ternary 1:1:1 complexes [Zn(II)(CysGly)(HisSer)] and [Zn(II)(CysGly)(HisPhe)] were shown by UV experiments, fluorescence titration, and gel electrophoresis to intercalate with DNA, and to hydrolytically cleave supercoiled DNA (form-I), partly also circular (form-II) DNA, under physiological conditions (37 degrees, H2O, pH 7.5).

Copper(II) complexes containing N,N-donor ligands and dipeptides act as hydrolytic DNA-cleavage agents.

Copper(II) complexes are known to play a significant role in both naturally occurring biological systems and pharmaceutical agents. Recently, Cu(II) complexes have gained importance in DNA cleavage essential for the development of anticancer drugs and chemotherapeutic agents. Therefore, we have designed small molecules, consisting of a metal ion, N,N-donor ligands, and dipeptides, to probe their DNA-cleaving potential. Accordingly, the interaction of Cu(II) with ethylenediamine, histamine and the dipeptides histidylglycine, histidylalanine, and histidylleucine has been investigated. The binding modes, stabilities, and geometries of these complexes were determined by various physicochemical techniques. Their DNA-binding abilities were probed by absorption and fluorescence spectroscopy, and their DNA-cleavage potential was tested by electrophoresis.