ABSTRACT
A series of ternary metal(ii) complexes {M(phen)(edda); 1a (Cu), 1b (Co), 1c (Zn), 1d (Ni); H(2)edda = N,N(')-ethylenediaminediacetic acid} of N,N'-ethylene-bridged diglycine and 1,10-phenanthroline were synthesized and characterized by elemental analysis, FTIR, UV-visible spectroscopy and magnetic susceptibility measurement. The interaction of these complexes with DNA was investigated using CD and EPR spectroscopy. MTT assay results of 1a-1c , screened on MCF-7 cancer cell lines, show that synergy between the metal and ligands results in significant enhancement of their antiproliferative properties. Preliminary results from apoptosis and cell cycle analyses with flow cytometry are reported. seems to be able to induce cell cycle arrest at G(0)/G(1). The crystal structure of 1a is also included.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , DNA/chemistry , Intercalating Agents/chemical synthesis , Intercalating Agents/pharmacology , Metals/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Circular Dichroism , Crystallography, X-Ray , Electron Spin Resonance Spectroscopy , Humans , Intercalating Agents/chemistry , Ligands , Male , SalmonABSTRACT
DNA fiber EPR was used to investigate the DNA binding stabilities and orientations of Cu(II).Gly-Gly-His-derived metallopeptides containing D- vs. L-amino acid substitutions in the first peptide position. This examination included studies of Cu(II).D-Arg-Gly-His and Cu(II).D-Lys-Gly-His for comparison to metallopeptides containing L-Arg/Lys substitutions, and also the diastereoisomeric pairs Cu(II).D/L-Pro-Gly-His and Cu(II).D/L-Pro-Lys-His. Results indicated that L-Arg/Lys to D-Arg/Lys substitutions considerably randomized the orientation of the metallopeptides on DNA, whereas the replacement of L-Pro by D-Pro in Cu(II).L-Pro-Gly-His caused a decrease in randomness. The difference in the extent of randomness observed between the D- vs. L-Pro-Gly-His complexes was diminished through the substitution of Gly for Lys in the middle peptide position, supporting the notion that the epsilon-amino group of Lys triggered further randomization, likely through hydrogen bonding or electrostatic interactions that disrupt binding of the metallopeptide equatorial plane and the DNA. The relationship between the stereochemistry of amino acid residues and the binding and reaction of M(II).Xaa-Xaa'-His metallopeptides with DNA are also discussed.
