Spectral and molecular docking studies of nucleic acids/protein binding interactions of a novel organometallic palladium (II) complex containing bioactive PTA ligands: Its synthesis,anticancer effects and encapsulation in albumin nanoparticles

The organometallic palladium complex with nitrogen-containing heterocycles is a potent antitumor agent. Coordination of phosphorus ligands to organometallic complexes increases their hydrophilicity, promotes ligand−DNA interactions and damage level to cancer cells, and blocks division in target cells. In this study, a phosphaadamantane palladium complex ([Pd{(C,N)- (C₁₂H₈NH₂)} (PTA) Cl], PTA = 1,3,5-Triaza-7-phosphaadamantane) ( 2 ) was synthesized via the reaction of biologically active PTA with binuclear palladacycles [Pd₂{(C,N)-(C₁₂H₈NH₂)}₂(μ-Cl)₂] ( 1 ). In vitro studies of the complex with DNA (calf-thymus) explored by UV–Vis, emission titration, circular dichroism and helix melting methods showed that the complex interacts with DNA via an intercalative mechanism. Furthermore, competitive binding studies using warfarin, digoxin and ibuprofen site markers containing definite binding sites revealed the binding of the complex to site I on bovine serum albumin. The in vitro release mechanism of the palladium complex exhibited a biphasic pattern characterized by an initial burst release followed by a slower sustained release. Ultimately, in vitro evaluation of cytotoxicity and cell death showed that the complexes were able to decrease the viability of human cancer cell lines (MCF-7 and Jurkat) in a dose-dependent manner, but lower decreases were observed in the viability of normal fibroblast cells ASF-4 at the dosages evaluated. Finally, the order of in vitro anticancer activities was found to be consistent with the DNA-binding affinities.     

Thiolate bridging and metal exchange in adducts of a zinc finger model and Pt(II) complexes: biomimetic studies of protein/Pt/DNA interactions

To provide precedents for the possible interactions of platinum DNA adducts with zinc finger proteins, the complexes [Pt(dien)Cl]Cl (dien = diethylenetriamine) and [Pt(terpy)Cl]Cl (terpy = 2,2':6',2'-terpyridine) were exposed to the N,N'-bis(2-mercaptoethyl)-1,4-diazacycloheptanezinc(II) dimer, [Zn(bme-dach)]2, and the products defined by electrospray ionization mass spectrometry (ESI-MS), X-ray crystallography and (195)Pt NMR spectroscopy. The presence of a leaving chloride in both platinum(II) complexes facilitates electrophilic substitution involving sulfur-containing zinc finger synthetic models or, as in previous studies, zinc finger peptidic sequences. Monitored via ESI-MS, both reactants yielded evidence for Zn-(mu-SR)-Pt bridges followed by zinc ejection from the N2S2 coordination sphere and subsequent formation of a trimetallic Zn-(mu-SR)2-Pt-(mu-SR)2-Zn-bridged species. The isolation of Zn-(mu-SR)-Pt-bridged species [(Zn(bme-dach)Cl)(Pt(dien))]Cl is, to our knowledge, the first Zn-Pt bimetallic thiolate-bridged model demonstrating the interaction between Zn-bound thiolates and Pt(2+). In the case of the [Pt(terpy)Cl]Cl reaction with the [Zn(bme-dach)]2, ESI-MS analysis further suggests metal exchange by formation of [Zn(terpy)Cl](+), whereas the [Pt(dien)Cl]Cl reaction does not yield the corresponding [Zn(dien)Cl](+) ion. Direct synthesis of the Zn-Pt thiolate-bridged species and the Pt(N2S2) chelate, where Pt has displaced the Zn from the chelate core, permitted the isolation of X-ray-quality crystals to confirm the bridging and metal-exchanged structures. The ESI-MS, (195)Pt NMR spectroscopy, and molecular structures of the di- and trinuclear complexes will be discussed, as they provide insight into the metal-exchange mechanism.     

Understanding sterol-membrane interactions, part II: complete 1H and 13C assignments by solid-state NMR spectroscopy and determination of the hydrogen-bonding partners of cholesterol in a lipid bilayer

The complete assignment of cholesterol 1H and 13C NMR resonances in a lipid bilayer environment (Lalpha-dimyristoylphosphatidylcholine/cholesterol 2:1) has been obtained by a combination of 1D and 2D MAS NMR experiments: 13C spectral editing, ge-HSQC, dipolar HETCOR and J-based HETCOR. Specific chemical shift variations have been observed for the C1-C6 atoms of cholesterol measured in CCl4 solution and in the membrane. Based on previous work (F. Jolibois, O. Soubias, V. Reat, A. Milon, Chem. Eur. J. 2004, 10, preceding paper in this issue: DOI: 10.1002/chem.200400245) these variations were attributed to local changes around the cholesterol hydroxy group, such as the three major rotameric states of the C3-O3 bond and different hydrogen bonding partners (water molecules, carboxy and phosphodiester groups of phosphatidylcholine). Comparison of the experimental and theoretical chemical shifts obtained from quantum-chemistry calculations of various transient molecular complexes has allowed the distributions of hydrogen bonding partners and hydroxy rotameric states to be determined. This is the first time that the probability of hydrogen bonding occurring between cholesterol's hydroxy group and phosphatidylcholine's phosphodiester has been determined experimentally.     

Equilibrium studies on binary and ternary Cu(II) complexes containing ethylenediaminediacetic acid and a series of O?-O?, N-O? and N-N donor ligands

The formation constants for ternary metal complexes (MLA) where L = ethylenediaminediacetic acid (EDDA), M = Cu(II) and A = glycine, alanine, leucine, serine, threonine, methionine, proline, phenylalanine, tryptophan, histidine, aspartic acid, ethylenediamine, histamine, 2,2′-bipyridyl, 1,10-phenanthroline, imidazole, oxalic acid, malonic acid, pyrocatechol and nitropyrocatechol have been investigated by pH-metric method at 35°C andμ = 0.2 M (KNO₃). With respect to the donor atoms on ligand A, the stabilities of the ternary complexes increase in the order O⁻-O⁻ < N-O⁻≈N-N. The stabilities of the various ternary complexes decrease with the increasing number of carboxylate groups on the ligand in the order ethylenediamine (EN) < ethylenediamine monoacetic acid (EDMA) < EDDA. Various factors influencing the formation and stabilities of ternary complexes are discussed.