Pd(II) Binding Strength of a Novel Ambidentate Dipeptide-Hydroxypyridinonate Ligand: A Solution Equilibrium Study.

A novel ambidentate dipeptide conjugate (H(L1)) containing N-donor atoms of the peptide part and an (O,O) chelate at the hydroxypyridinone (HP) ring is synthesized and characterized. It is hoped that this chelating ligand can be useful to obtain multitargeted Co(III)/Pt(II) dinuclear complexes with anticancer potential. The Pd(II) (as a Pt(II) model but with faster ligand exchange reactions) binding strength of the ligand was studied in an aqueous solution with the combined use of pH-potentiometry and NMR. In an equimolar solution, (L1)- was found to bind Pd(II) via the terminal amino and increasing number of peptide nitrogens of the peptide backbone over a wide pH range. At a 2:1 Pd(II) to ligand ratio, the presence of [Pd2H-x(L1)] (x = 1-4) species, with high stability and with the coordination of the (O,O) chelating set of the ligand, was detected. The reaction of H(L1) with [Co(tren)]3+ (tren = tris(2-aminoethyl)amine) indicated the exclusive binding of (L1)- via its (O,O) donor atoms to the metal unit, while treatment of the resulting Co-complex with Pd(II) afforded the formation of a Co/Pd heterobimetallic complex in solution with an (NH2, Namide) coordination of Pd(II). Shortening the peptide backbone in H(L1) by one peptide unit compared to the structurally similar ambidentate chelator consisting of three peptide bonds resulted in the slightly more favorable formation of the N-coordinated Pd(II) species, allowing the tailoring of the coordination properties.

Trends and Exceptions in the Interaction of Hydroxamic Acid Derivatives of Common Di- and Tripeptides with Some 3d and 4d Metal Ions in Aqueous Solution.

By using various techniques (pH-potentiometry, UV-Visible spectrophotometry, 1H and 17O-NMR, EPR, ESI-MS), first time in the literature, solution equilibrium study has been performed on complexes of dipeptide and tripeptide hydroxamic acids-AlaAlaNHOH, AlaAlaN(Me)OH, AlaGlyGlyNHOH, and AlaGlyGlyN(Me)OH-with 4d metals: the essential Mo(VI) and two half-sandwich type cations, [(η6-p-cym)Ru(H2O)3]2+ as well as [(η5-Cp*)Rh(H2O)3]2+, the latter two having potential importance in cancer therapy. The tripeptide derivatives have also been studied with some biologically important 3d metals, such as Fe(III), Ni(II), Cu(II), and Zn(II), in order to compare these new results with the corresponding previously obtained ones on dipeptide hydroxamic acids. Based on the outcomes, the effects of the type of metal ions, the coordination number, the number and types of donor atoms, and their relative positions to each other on the complexation have been evaluated in the present work. We hope that these collected results might be used when a new peptide-based hydroxamic acid molecule is planned with some purpose, e.g. to develop a potential metalloenzyme inhibitor.

Speciation in human blood of Metvan, a vanadium based potential anti-tumor drug.

The first report on the anti-cancer activity of the compound Metvan, [VIVO(Me2phen)2(SO4)], where Me2phen is 4,7-dimethyl-1,10-phenanthroline, dates back to 2001. Although it was immediately identified as one of the most promising multitargeted anti-cancer V compounds, no development on the medical experimentation was carried out. One of the possible reasons is the lack of information on its speciation in aqueous solution and its thermodynamic stability, factors which influence the transport in the blood and the final form which reaches the target organs. To fill this gap, in this work the speciation of Metvan in aqueous solution and human blood was studied by instrumental (EPR, electronic absorption spectroscopy, ESI-MS and ESI-MS/MS), analytical (pH-potentiometry) and computational (DFT) methods. The results suggested that Metvan transforms at physiological pH into the hydrolytic species cis-[VO(Me2phen)2(OH)]+ and that both citrate and proteins (transferrin and albumin in the blood serum, and hemoglobin in the erythrocytes) form mixed complexes, denoted [VO(Me2phen)(citrH-1)]2- and VO-Me2phen-Protein with the probable binding of His-N donors. The measurements with erythrocytes suggest that Metvan is able to cross their membrane forming mixed species VO-Me2phen-Hb. The redox stability in cell culture medium was also examined, showing that ca. 60% is oxidized to VV after 5 h. Overall, the speciation of Metvan in the blood mainly depends on the V concentration: when it is larger than 50 µM, [VO(Me2phen)(citrH-1)]2- and VO-Me2phen-Protein are the major species, while for concentrations lower than 10 µM, (VO)(hTf) is formed and Me2phen is lost. Therefore, it is plausible that the pharmacological activity of Metvan could be due to the synergic action of free Me2phen, and VIVO and VVO/VVO2 species.

Biorelevant reactions of the potential anti-tumor agent vanadocene dichloride.

The interaction of the potential anti-tumor agent vanadocene dichloride ([Cp2VCl2] or VDC) with some relevant bioligands of the cytosol such as proteins (Hb), amino acids (glycine and histidine), NADH derivatives (NADH, NADPH, NAD(+) and NADP(+)), reductants (GSH and ascorbic acid), phosphates (HPO4(2-), P2O7(4-), cAMP, AMP, ADP and ATP) and carboxylate derivatives (lactate) and its uptake by red blood cells were studied. The results indicated that [Cp2VCl2] transforms at physiological pH into [Cp2V(OH)2] and that only HPO4(2-), P2O7(4-), lactate, ATP and ADP form mixed species with the [Cp2V](2+) moiety replacing the two hydroxide ions. EPR and electronic absorption spectroscopy, agarose gel electrophoresis and spin trapping measurements allow excluding any direct interaction and/or intercalation with DNA and the formation of reactive oxygen species (ROS) in Fenton-like reactions. Uptake experiments by erythrocytes suggested that VDC crosses the membrane and enters inside the cells, whereas 'bare' V(IV) transforms into V(IV)O species with loss of the two cyclopentadienyl rings. This transformation in the cellular environment could be related to the mechanism of action of VDC.

Complex formation between Ru(η(6)-p-cym)(H2O)3]2+ and (O,O) donor ligands with biological relevance in aqueous solution.

The interaction between [Ru(η(6)-p-cym)(H(2)O)(3)](2+) and (O,O) type chelators with different basicity of the donor atoms was studied using combined pH-potentiometric, (1)H-NMR and ESI-TOF-MS techniques. The studied nine ligands are building blocks of reported complexes with antitumor activity or may model (O,O) donor serum components capable of interacting with the administered half-sandwich ruthenium(II) type drug. Composition and stability constants of the [Ru(η(6)-p-cym)(O,O)Y] type species (Y: H(2)O or OH(-)) were determined (T = 25.0 °C; I = 0.20 M (KCl)) and the metal ion binding strengths of the ligands are discussed. It was found that ligands with two low basicity O donors (oxalic and cyclobutane-1,1-dicarboxylic acid) bind the metal ion at acidic conditions but are not able to prevent the hydrolysis at physiologically relevant conditions. Ligands with one low and one high basicity O donor (lactic and salicylic acid) are weak binders for Ru(η(6)-p-cym)(H(2)O)(3)](2+). Pyrone or pyridinone based ligands are capable of binding the metal ion over a wide pH range and no hydrolysis product is detectable at pH = 7.4. The obtained speciation models may help in the rationalization of the biological activity of such complexes and provide a deeper insight into the solution behaviour of half-sandwich Ru(II) complexes with potential anticancer activity.