Interaction between [(η6-p-cym)M(H2O)3]2+ (MII = Ru, Os) or [(η5-Cp*)M(H2O)3]2+ (MIII = Rh, Ir) and Phosphonate Derivatives of Iminodiacetic Acid: A Solution Equilibrium and DFT Study.

The pH-dependent binding strengths and modes of the organometallic [(η6-p-cym)M(H2O)3]2+ (MII = Ru, Os; p-cym = 1-methyl-4-isopropylbenzene) or [(η5-Cp*)M(H2O)3]2+ (MIII = Rh, Ir; Cp* = pentamethylcyclopentadienyl anion) cations towards iminodiacetic acid (H2Ida) and its biorelevant mono- and diphosphonate derivatives N-(phosphonomethyl)-glycine (H3IdaP) and iminodi(methylphosphonic acid) (H4Ida2P) was studied in an aqueous solution. The results showed that all three of the ligands form 1:1 complexes via the tridentate (O,N,O) donor set, for which the binding mode was further corroborated by the DFT method. Although with IdaP3- and Ida2P4- in mono- and bis-protonated species, where H+ might also be located at the non-coordinating N atom, the theoretical calculations revealed the protonation of the phosphonate group(s) and the tridentate coordination of the phosphonate ligands. The replacement of one carboxylate in Ida2- by a phosphonate group (IdaP3-) resulted in a significant increase in the stability of the metal complexes; however, this increase vanished with Ida2P4-, which was most likely due to some steric hindrance upon the coordination of the second large phosphonate group to form (5 + 5) joined chelates. In the phosphonate-containing systems, the neutral 1:1 complexes are the major species at pH 7.4 in the millimolar concentration range that is supported by both NMR and ESI-TOF-MS.

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.

Diversity in the Interaction of Amino Acid- and Peptide-Based Hydroxamic Acids with Some Platinum Group Metals in Solution.

Complexes that incorporate both ligand(s) and metal(s) exhibiting cytotoxic activity can especially be interesting to develop multifunctional drug molecules with desired activities. In this review, the limited number of solution results collected in our laboratory on the complexes of Pd(II) and two other platinum group metals-the half-sandwich type, [(η6-p-cym)Ru(H2O)3]2+, and [(η5-Cp*)Rh(H2O)3]2+-with hydroxamic acid derivatives of three amino acids, two imidazole analogues, and four small peptides are summarized and evaluated. Unlike the limited number of coordination sites of these metal ions (four and three for Pd(II) and the organometallic cations, respectively), the ligands discussed here offer a relatively high number of donor atoms as well as variation in their position within the ligands, resulting in a large versatility of the likely coordination modes. The review, besides presenting the solution equilibrium results, also discusses the main factors, such as (N,N) versus (O,O) chelate; size of chelate; amino-N versus imidazole-N; primary versus secondary hydroxamic function; differences between hydrolytic ability of the metal ions studied; and hydrolysis of the coordinated peptide hydroxamic acids in their Pd(II) complexes, which all determine the coordination modes present in the complexes formed in measurable concentrations in these systems. The options for the quantitative evaluation of metal binding effectivity and selectivity of the various ligands and the comparison with each other by using solution equilibrium data are also discussed.

Factors Determining the Metal Ion Binding Ability and Selectivity of Hydroxamate-Based Compounds.

There has been a long tradition for a broad spectrum of applications of both natural and synthetic hydroxamic acids and derivatives. Even nowadays, a huge number of newly designed representatives (from different monohydroxamate-based compounds to siderophore conjugates) are used to develop potential drug candidates with desired activities. Since these compounds are effective metal-chelating agents, their biological roles and actions as well as their various applications, e.g., in the medicinal practice, are all in direct correlation with their metal complexation. Consequently, the knowledge of the stoichiometry and binding modes of metal complexes with hydroxamic acid-based ligands, their thermodynamic parameters, and speciation profiles in solution are crucial for scientists working in any of the above-mentioned fields. This review, in addition to presenting a few factors, which might affect the metal-binding capabilities of these organic ligands, displays and summarizes the different parameters typically used to give the stoichiometry, composition, and stability of the species formed in a solution equilibrium system in measurable concentration. Discussion of the possibilities for quantitative comparison of metal-binding effectivity and selectivity of various hydroxamic acids with each other by using solution equilibrium data is also the focus of this publication.

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.

Characterization and biotransformation in the plasma and red blood cells of V(IV)O(2+) complexes formed by ceftriaxone.

The coordination mode and geometry in aqueous solution of oxidovanadium(IV) complexes formed by a third-generation cephalosporin, ceftriaxone (H3cef), were studied by spectroscopic (EPR, electron paramagnetic resonance), pH-potentiometric and computational (DFT, density functional theory) methods. The behavior of the model systems containing 6-hydroxy-2-methyl-3-thioxo-3,4-dihydro-1,2,4-triazine-5(2H)-one (H2hmtdt) and 3-benzylthio-6-hydroxy-2-methyl-1,2,4-triazine-5(2H)-one (Hbhmt) was examined for comparison. The stability of the tautomers of ceftriaxone and 6-hydroxy-2-methyl-3-thioxo-3,4-dihydro-1,2,4-triazine-5(2H)-one in the neutral, mono- and bi-anionic form was calculated by DFT methods, both in the gas phase and in aqueous solution, and the electron density on the oxygen atoms of the hydroxytriazinone ring was related to the pKa of the ligands. The data demonstrate that ceftriaxone coordinates V(IV)O(2+) forming mono- and bis-chelated complexes with (Oket, O(-)) donor set and formation of five-membered chelate rings. The geometry of the bis-chelated complex, cis-[VO(Hcef)2(H2O)](2-), is cis-octahedral and this species can deprotonate, around physiological pH, to form the corresponding mono-hydroxido cis-[VO(Hcef)2(OH)](3-). The interaction of cis-[VO(Hcef)2(H2O)](2-) with apo-transferrin (apo-hTf) was studied and the results suggest that V(IV)O(2+) distributes between (VO)apo-hTf/(VO)2apo-hTf and cis-[VO(Hcef)2(H2O)](2-), whereas mixed complexes are not formed for charge and steric effects. The interaction of cis-[VO(Hcef)2(H2O)](2-) with red blood cells shows that ceftriaxone helps V(IV)O(2+) ion to cross the erythrocyte membrane. Inside the cell cis-[VO(Hcef)2(H2O)](2-) decomposes and the same species formed by inorganic V(IV)O(2+) are observed. The relationship between the biotransformation in the plasma and red blood cells and the potential pharmacological activity of V(IV)O(2+) species of ceftriaxone is finally discussed.

Interaction of [Ru(η6-p-cym)(H2O)3]²âº with citrate and tricarballate ions in aqueous solution; X-ray crystal structure of novel half-sandwich Ru(II)-citrato complexes.

The interaction between [Ru(η(6)-p-cym)(H(2)O)(3)](2+) and an important low molecular weight serum component, citric acid (citrH(3)), was studied with the aid of combined pH-potentiometric, (1)H NMR, (13)C NMR and electrospray ionization mass spectrometry (ESI-MS) methods in aqueous solution. For comparative purposes propane-1,2,3-tricarboxylic acid (tricarballylic acid, tricH(3)) having no alcoholic-OH group in position 2 was also investigated. Stoichiometries, stability constants and the most plausible solution structures of the complexes formed in the systems were determined. Depending upon the pH, citrate was found to coordinate to the metal ion via [COO(-), COO(-), OH] or [COO(-), COO(-), O(-)] fashion yielding mononuclear complexes with high stability. As a consequence at physiological pH the hydrolysis of the metal ion is completely hindered even at 1:1 metal to ligand ratio. Crucial role of the alcoholic/alcoholate function of the citric acid in [Ru(η(6)-p-cym)(H(2)O)(3)](2+) binding is reflected in the low stability of the species formed with tricarballylic acid. The X-ray crystal structures of [Ru(η(6)-p-cym)(citrH)]·H(2)O·CH(3)OH and 2[Ru(η(6)-p-cym)(citrH)]·3H(2)O being the first published structures of an organometallic Ru(II)-citrate and both featuring a [COO(-), COO(-), OH] coordinated ligand, are also reported.

Transport of the anti-diabetic VO2+ complexes formed by pyrone derivatives in the blood serum.

The biotransformation in the blood serum of the two anti-diabetic agents [VO(ema)(2)] - or BEOV - and [VO(koj)(2)] formed by ethylmaltol (Hema) and kojic acid (Hkoj) was studied with EPR spectroscopy, pH-potentiometry and DFT calculations. For comparison, the behavior of the systems with tropolone (Htrop) was also analyzed. The interaction of [VO(ema)(2)] and [VO(koj)(2)] with the most important bioligands of the serum, lactic (Hlact) and citric acid (H(3)citr), human serum transferrin (hTf), human serum albumin (HSA) and immunoglobulin G (IgG) was examined and discussed. Among the several mixed species observed, cis-VO(carrier)(2)(hTf), cis-VO(carrier)(2)(HSA) and cis-VO(carrier)(2)(IgG), where carrier is ethylmaltolate or kojate, with a His-N of the protein coordinated in the equatorial position, are plausible candidates for the transport processes of the drug toward the target organs. The values of the logß are in the range 19.6-19.8 for the species formed by ethylmaltol and 17.4-17.6 for those formed by kojic acid. The formation of such species was confirmed through pH-titrations of the model systems VO(2+)/carrier/1-MeIm and VO(2+)/carrier/Ac-his, where 1-MeIm and Ac-his are 1-methylimidazole and N-acetylhistamine, and DFT calculations of (51)V A(z) of the model species cis-[VO(carrier)(2)(1-MeIm)] and cis-[VO(carrier)(2)(Ac-his)]. The values of the stability constants for the mixed species observed were used to predict the biodistribution of VO(2+) ion between the blood serum components for concentrations of 1, 10 and 50 µM.

Hydrolytic behaviour and chloride ion binding capability of [Ru(η6-p-cym)(H2O)3]2+: a solution equilibrium study.

Hydrolysis of an organometallic cation, [Ru(η(6)-p-cym)(H(2)O)(3)](2+) (p-cym = 1-isopropyl-4-methylbenzene), in the presence of 0.20 M KNO(3) or KCl as supporting electrolyte was studied in detail with the combined use of pH-potentiometry, (1)H-NMR, UV-VIS and ESI-TOF-MS. Stoichiometry and stability constants of chlorido, hydroxido and mixed chlorido-hydroxido complexes formed in aqueous solution have been determined. At pH < 4.0 where hydrolysis of [Ru(η(6)-p-cym)(H(2)O)(3)](2+) is negligible with increasing chloride ion concentration two chlorido complexes, [Ru(η(6)-p-cym)(H(2)O)(2)Cl](+) and [{Ru(η(6)-p-cym)}(2)(µ(2)-Cl)(3)](+), are detectable. At pH > 5.0, in chloride ion free samples the exclusive formation of [{Ru(η(6)-p-cym)}(2)(µ(2)-OH)(3)](+) is found. However, if chloride ion is present (in the range 0-3.50 M) novel mixed chlorido-hydroxido species, [{Ru(η(6)-p-cym)}(2)(µ(2)-OH)(2)(µ(2)-Cl)](+) and [{Ru(η(6)-p-cym)}(2)(µ(2)-OH)(µ(2)-Cl)(2)](+) can also be identified at pH > 4.0. The results obtained in this study may help in rationalizing the solution behaviour of half-sandwich [Ru(η(6)-p-cym)(XY)Z] type complexes which, after dissociation of both the monodentate Z and the chelating XY, are capable of yielding the free aqua species [Ru(η(6)-p-cym)(H(2)O)(3)](2+). Our results demonstrate that different chloride ion concentrations can influence the speciation in the acidic pH range but at biologically relevant conditions (pH = 7.4, c(Cl(-)) = 0.16 M) and at c(M) = 1 µM [{Ru(η(6)-p-cym)}(2)(µ(2)-OH)(3)](+) is predominant in the absence of any coordinating ligands.

Biotransformation of BMOV in the presence of blood serum proteins.

The interaction of the potent anti-diabetic agent bis(maltolato)oxidovanadium(IV) (BMOV) with some proteins of blood serum was studied by EPR spectroscopy, pH-potentiometry and DFT calculations. The formation of cis-VO(ma)(2)(hTf), cis-VO(ma)(2)(HSA) and cis-VO(ma)(2)(IgG), their role in the biotransformation in vivo and the mechanism of transport of BMOV in blood are discussed.

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.