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.
Reddy
Pulimamidi R
PR
Department of Chemistry, Osmania University, Hyderabad-500 007, India. rabi_pr@rediffmail.com
Rao
Kandibanda S
KS
D053837:DNA Cleavage / Q000187:drug effects*; D006868:Hydrolysis / Q000187:drug effects; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry* / Q000494:pharmacology*
D009532:Nickel