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.

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.

Donor Atom Preference of Organoruthenium and Organorhodium Cations on the Interaction with Novel Ambidentate (N,N) and (O,O) Chelating Ligands in Aqueous Solution.

Two novel, pyridinone-based chelating ligands containing separated (O,O) and (Namino,Nhet) chelating sets (Namino = secondary amine; Nhet = pyrrole N for H(L3) (1-(3-(((1H-pyrrole-2-yl)methyl)-amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one) or pyridine N for H(L5) (3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one)) were synthesized via reduction of the appropriate imines. Their proton dissociation processes were explored, and the molecular structures of two synthons were assessed by X-ray crystallography. These ambidentate chelating ligands are intended to develop Co(III)/PGM (PGM = platinum group metal) heterobimetallic multitargeted complexes with anticancer potential. To explore their metal ion binding ability, the interaction with Pd(II), [(η6-p-cym)Ru]2+ and [(η5-Cp*)Rh]2+ (p-cym = 1-methyl-4-isopropylbenzene, Cp* = pentamethyl-cyclopentadienyl anion) cations was studied in aqueous solution with the combined use of pH-potentiometry, NMR and HR ESI-MS. In general, organorhodium was found to form more labile complexes over ruthenium, while complexation of the (N,N) chelating set was slower than the processes of the pyridinone unit with (O,O) coordination. Formation of the organoruthenium complexes starts at lower pH (higher thermodynamic stabilities of the corresponding complexes) than for [(η5-Cp*)Rh]2+ but, due to the higher affinity of [η6-p-cym)Ru]2+ towards hydrolysis, the complexed ligands are capable of competing with hydroxide ion in a lesser extent than for the rhodium systems. As a result, under biologically relevant conditions, the rhodium binding effectivity of the ligands becomes comparable or even slightly higher than their effectivity towards ruthenium. Our results indicate that H(L3) is a less efficient (N,N) chelator for these metal ions than H(L5). Similarly, due to the relative effectivity of the (O,O) and (N,N) chelates at a 1:1 metal-ion-to-ligand ratio, H(L5) coordinates in a (N,N) manner to both cations in the whole pH range studied while, for H(L3), the complexation starts with (O,O) coordination. At a 2:1 metal-ion-to-ligand ratio, H(L3) cannot hinder the intensive hydrolysis of the second metal ion, although a small amount of 2:1 complex with [(η5-Cp*)Rh]2+ can also be detected.

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.

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.

Synthesis, characterization and cytotoxicity studies of Co(III)-flavonolato complexes.

Hypoxia activated Co(III) complexes as prodrugs may provide with a selective delivery of cytotoxic or antibacterial compounds. Whithin this field sixteen novel Co(III) ternary complexes with the general formula [Co(4N)(flav)](ClO4)2, where 4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa) and flav = deprotonated form of differently substituted flavonols have been synthesized, characterized, and their cytotoxicity assayed under both normoxic and hypoxic conditions. Molecular structures of two free flavonols and seven complexes are also reported. In all the complexes the bioligands exhibited the expected (O,O) coordination mode and the complexes showed a slightly distorted octahedral geometry. Cyclic voltammetric studies revealed that both the substituents of the flavonoles and the type of 4N donor ligands had an impact on the reduction potential of the complex. The ones containing tren demonstrated significantly higher stability than the tpa analogues, making these former compounds promising candidates for the development of hypoxia-activated prodrug complexes. Tpa complexes showed higher activity against both selected human cancer cell lines (A549, A431) than their free ligand flavonols, indicating that the anticancer activity of the bioligand can be enhanced upon complexation. However, slight hypoxia-selectivity was found only for a tren complex (11) with moderate cytotoxicity.

Synthesis, characterization and albumin binding capabilities of quinizarin containing ternary cobalt(III) complexes.

Four Co(III) ternary complexes with the composition of [(Co(4 N))2(quin)](ClO4)4 or [(Co(4 N))2(quinS)](ClO4)3, where 4 N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa), quinH2 = quinizarin (1,4-dihydroxy-9,10-anthraquinone), quinSH3 = quinizarin-2-sulfonic acid (1,4-dihydroxy-9,10-anthraquinone-2-sulfonic acid), were synthesized, characterized and their human serum albumin (HSA) binding capabilities were also tested. The complexes can be considered as likely chaperons of quinizarins which are structural models for anthracycline-based anticancer drugs like doxorubicin. All the Co(III) complexes are dinuclear and were isolated as mixture of isomers. Comparison of the cyclic voltammograms of the free ligands and the appropriate Co(III) complexes revealed that the new signals belonging to reversible processes in the range -400-0 mV (vs. Ag/AgCl) for the complexes can be attributed to the reversible reduction of the Co(III) centre. These potentials are in the range of typical (O,O) chelated Co(III) ternary complexes bearing 4 N donor ligands and follow the order being more positive for the tpa containing complexes. Presence of the sulfonate group in the quinizarin results in slightly more negative reduction potential of the Co(III) complexes. HSA binding capabilities of the quinH2 and quinSH3 ligands as well as the appropriate complexes showed that quinSH3 has higher affinity to the protein than quinH2 while none of the complexes seem to bind to HSA.

Synthesis, characterization and biological evaluation of Co(III) complexes with quinolone drugs.

Nine novel cobalt(III) ternary complexes bearing 4N donor ligands (tris(2-aminoethyl)amine (tren) or tris(2-methylpyridyl)amine (tpa)) and (fluoro)quinolones (quinH) with antibacterial and potential antitumor activity have been synthesized, characterized and screened in various biological assays. The molecular structures of [Co(tpa)(nal)](PF6)2 (3) and [Co(tpa)(nor)(Co(tpa)(norH)](PF6)3(Cl)2∙5MeOH (8) (nal = deprotonated form of nalidixic acid, norH = norfloxacin) with the expected octahedral geometry and (O,O) coordination of the quinolone ligands are also reported. Cyclic voltammetric studies revealed that the 4N donor ligands have much higher effect on the reduction potential of these ternary complexes than the quinolones. Due to the π-back-bonding interaction of the metal ion with the pyridyl-N atoms, the tpa containing compounds demonstrated lower stability and were easier to get reduced in a reversible manner. This character makes them unlikely candidates for development of effective, highly selective hypoxia-activated pro-drug complexes, but this goal might be achieved by substitution of tpa by tren. [Co(tren)(cip)](PF6)2 (4) and [Co(tpa)(cip)](PF6)2 (5) (cip = deprotonated form of ciprofloxacin) showed slightly less antibacterial activity against Escherichia coli than free ciprofloxacin (cipH) and they found to have very low toxicity towards both selected cancer (HeLa, MCF 7, MDA-MB-239) and noncancerous (MRC5 pd30) cells. Interaction of 4 and 5 with calf thymus DNA studied by UV-Vis, flow linear dichroism, viscometry and DNA melting indicated the complexes to bind to DNA as intercalators. DNA electrophoresis revealed that, unlike Co(II) complexes, 4 and 5 are not capable of cleaving DNA, but they can inhibit bacterial DNA gyrase 5 being slightly more active than 4.

Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest.

Lead(II) forms (NH2,COO-)-chelated mono- and bis-complexes with simple amino acids, while mono-complexes with pH-dependent coordination modes exist with simple dipeptides. These mostly hemidirected complexes have moderate stability. While a weak interaction of side chain imidazole and carboxylate in lead(II)-aminoacidato complexes is found, the thiolate group has an exceptionally high affinity to this metal ion. For example, tridentate (NH2,COO-,S-)-coordination of penicillamine (Pen) and cysteine (Cys) results in an extremely strong interaction with lead(II), but, owing to the sterical effect of the 6s2 pair, a second ligand is not able to coordinate in the above mentioned tridentate way. Although there is no example for a lead(II)-induced deprotonation and coordination of a peptide-amide and the side-chain thiolate in oligopeptides has a somewhat lower basicity compared to that of Pen or Cys, still the Cys-containing peptides interact rather strongly with lead(II). Interestingly, the position of Cys in the peptide influences significantly both the lead-binding ability via different bonding modes and the selectivity for lead(II) against other metal ions, like zinc(II) or cadmium(II). At high ligand excess, however, coordination of three sulfur donors to lead(II) is found with thiolate-containing amino acids and oligopeptides. High basicity oxygens of hydroxamates, hydroxypyronates, and hydroxypyridinonates are also effective lead-binding donors. Some factors affecting the complexation of these ligands with lead(II) are: (i) A larger extent of delocalization along the ring in hydroxypyridinonate results in a more favored metal-binding ability over hydroxypyronate. (ii) Even monohydroxamates are good ligands and form mono- and bis-complexes with lead(II). (iii) In general, dihydroxamates and trihydroxamate-based siderophores, like desferrioxamine B (DFB) and desferricoprogen (DFC), are better binding agents for Pb(II) than the monohydroxamates, but the length and structure of linkers connecting the hydroxamate moieties have a significant impact on the complexation and selectivity for lead(II). (iv) The corresponding thio derivatives are significantly better ligands for lead than their parent oxo molecules, but polymeric complexes with poor water solubility are formed in most cases. (v) Out of the hydroxamate derivatives of amino acids the α-ones are the most effective ligands, provided polynuclear species involving the hydroxamate-oxygens, amino-N and hydroxamate-N can be formed.

Pb(II)-binding capability of aminohydroxamic acids: primary hydroxamic acid derivatives of alpha-amino acids as possible sequestering agents for Pb(II).

Complexes of aminohydroxamic acids, D,L-alpha-alaninehydroxamic acid (alpha-Alaha), sarcosinehydroxamic acid (Sarha), D,L-N-methyl-alpha-alaninehydroxamic acid (N-Me-alpha-Alaha), beta-alaninehydroxamic (beta-Alaha), L-aspartic acid-beta-hydroxamic acid (Asp-beta-ha), L-glutamic acid-gamma-hydroxamic acid (Glu-gamma-ha) and L-histidinehydroxamic acid (Hisha) with lead(II) in aqueous solution were studied by pH-potentiometric, 1H NMR and electrospray ionization mass spectrometric (ESI MS) methods. The results were compared to those of a simple monohydroxamic acid, acetohydroxamic acid and the effects of the amino group, hydroxamate-N, as well as, additional side chain donors on the co-ordination mode and on the stability of the complexes formed were evaluated. It was found that the amino nitrogen atom situating in beta- or in gamma-position (beta-Alaha, Asp-beta-ha, Glu-gamma-ha) does not co-ordinate to Pb(II), only hydroxamate type chelates are formed before the hydrolytic processes. However, the amino-N in alpha-position (alpha-Alaha, Sarha, Hisha) seems to form a stable 5-membered (N,N)-type chelate together with the deprotonated hydroxamate-N above pH 6. On the other hand, the hydroxamate (O,O)-type chelate also exists. Since steric reasons do not allow the coordination of these two chelates of a molecule to the same Pb(II) ion, polynuclear complexes with mixed co-ordination modes are formed with the alpha-derivatives above pH 6. Simple hydroxamate type complexes are formed with N-Me-alpha-Alaha, where the hydroxamate-N is not able to co-ordinate. The co-ordination of the side chain imidazole of Hisha is not measurable, while a weak interaction of the side chain carboxylates of Asp-beta-ha and especially of Glu-gamma-ha can be suggested.

Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer.

In the search for new cytotoxic drugs, two copper complexes with isomeric dipeptides (Ala-Phe and Phe-Ala) were developed in order to determine the influence of their different structures in the modulation of the chemical, biochemical and biological properties. Spectroscopic, voltammetric and equilibrium studies were performed providing information about the chemical properties. The superoxide dismutase (SOD) activity was studied and showed differences of IC50 for both Cu-Ala-Phe (IC50=4.5) and Cu-Phe-Ala (IC50=45). The computational results permitted to explain this behavior proposing that it is feasible that the O2- anion is attracted straight to the positive zone in Cu-Ala-Phe whereas for Cu-Phe-Ala this phenomenon would happen to a smaller extent. Confirming our previous studies, both complexes interacted with DNA. Molecular docking studies showed that the position of the phenyl ring modulates the complex-DNA affinity and in Cu-Ala-Phe the docked conformation allows the copper ion to face the DNA basis, giving rise to a more stable complex-DNA adduct than for Cu-Phe-Ala. In spite of the fact that Atomic Force Microscopy showed plasmid compactation and aggregation for both complexes, the image showed softer changes in the case of Cu-Ala-Phe in comparison with those produced by Cu-Phe-Ala. In order to evaluate the effect of Cu-Ala-Phe and Cu-Phe-Ala complexes against tumor cells, we have employed three aggressive metastatic breast adenocarcinoma cellular models, derived from human (MDA-MB-231 and MCF-7) and mouse (4T1) spontaneous tumors. These experiments showed that both Cu-dipeptide complexes have a similar cytotoxic effect against breast cancer cells, and lower toxicity against BJ non-tumor cells in comparison to Cisplatin.

Bis(3-hydroxy-4-pyridinone)-EDTA derivative as a potential therapeutic Al-chelating agent. Synthesis, solution studies and biological assays.

The 3-hydroxy-4-pyridinones are chelating agents of current interest due to their high affinity for hard metal ions and potential clinical applications as metal-decorporation agents. A new bis-(3-hydroxy-4-pyridinone) derivative of EDTA have been developed, and herein we describe the results of solution studies to determine the protonation constants and the partition coefficient. Biodistribution studies, performed with 67Ga-overload mice, showed rapid clearance of the radiotracer from the body, thus indicating that the new ligand should be a quite effective agent for the in vivo aluminium removal.

Solution equilibrium studies on metal complexes of 2,3-dihydroxy-phenylalanine-hydroxamic acid (Dopaha) and models: catecholate versus hydroxamate coordination in iron(III)-, aluminium(III)- and molybdenum(VI)-Dopaha complexes.

Equilibrium results based on pH potentiometric, spectrophotometric and (1)H NMR measurements for the complexes of Fe(III), Al(III) and Mo(VI) with 2,3-dihydroxy-phenylalanine-hydroxamic acid (Dopaha) as well as for binary model systems Fe(III)-, Al(III)-, Mo(VI)-acetohydroxamic acid (Aha), -alpha-alaninehydroxamic acid (alpha-Alaha) and -1,2-dihydroxy-3,5-benzene-disulphonate (Tiron) and ternary model systems Fe(III)-, Al(III)-, Mo(VI)-Tiron-Aha, are summarized in this paper. The amine-type coordination mode is not detectable with these metal ions at all. Precipitation occurs at pH <5.5 with Fe(III) and Al(III) even at a Dopaha-to-metal ion ratio of 10:1. Hydroxamate-type coordination was demonstrated with both metals below the pH range of precipitation but, after dissolution, catecholate-type coordination was exclusively found. The hydroxamate-type coordination mode occurs only in the very acidic pH range for Mo(VI) complexes and the crossover from hydroxamate to catecholate binding occurs at pH >3. A ligand-bridged dinuclear species, [(MoO(2))(2)(Dopaha)(2)](2+), involving mixed-type (catecholate and hydroxamate) coordination modes is formed in the pH range 2.5-5.5. [MoO(2)A(2)H(2)], with catecholate-type coordination, forms above pH 3. On increasing the pH further, deprotonation of the coordinated Dopaha and hydrolytic processes result in the formation of catecholate-coordinated [MoO(3)AH] and [MoO(3)A]. MoO(4)(2-) and free Dopaha exist above pH 10.

Complexation of desferricoprogen with trivalent Fe, Al, Ga, In and divalent Fe, Ni, Cu, Zn metal ions: effects of the linking chain structure on the metal binding ability of hydroxamate based siderophores.

Complexes of the natural siderophore, desferricoprogen (DFC), with several trivalent and divalent metal ions in aqueous solution were studied by pH-potentiometry, UV-Vis spectrophotometry and cyclic voltammetry. DFC was found to be an effective metal binding ligand, which, in addition to Fe(III), forms complexes of high stability with Ga(III), Al(III), In(III), Cu(II), Ni(II) and Zn(II). Fe(II), however, is oxidized by DFC under anaerobic conditions and Fe(III) complexes are formed. By comparing the results with those of desferrioxamine B (DFB), it can be concluded that the conjugated beta-double bond slightly increases the stability of the hydroxamate chelates, consequently increases the stability of mono-chelated complexes of DFC. Any steric effect by the connecting chains arises only in the bis- and tris-chelated complexes. With metal ions possessing a relatively big ionic radius (Cu(II), Ni(II), Zn(II), In(III)) DFC, containing a bit longer chains than DFB, forms slightly more stable complexes. With smaller metal ions the trend is the opposite. Also a notable difference is that stable trinuclear complex, [Cu(3)L(2)], is formed with DFC but not with DFB. Possible bio-relevance of the Fe(II)/Fe(III) results is also discussed in the paper.

Mn(II)/Mn(III) and Fe(III) binding capability of two Aspergillus fumigatus siderophores, desferricrocin and N', N″, N‴-triacetylfusarinine C.

Manganese(II) and manganese(III) complexes of the exocyclic desferricrocin (H3DFCR) and endocyclic triacetylfusarinine C (H3TAF) in solution have been studied by using pH-potentiometry, UV-Vis spectrophotometry, relaxometry and cyclic voltammetry. A comparison between the present results and the corresponding ones for the open-chain analogues, desferrioxamine B (DFB) and desferricoprogen (DFC), shows (i) The dissociation processes of H3DFCR occur in the expected pH-range (pH7-10.5), but hydrogen bonding is assumed to be responsible for a quite low proton dissociation constant (pK=4.18) of H3TAF and also an unusually high one (10.59). (ii) Moderate stability complexes with 1:1 Mn(II) to ligand ratio are formed with all four siderophores. (iii) The coordination of the three hydroxamates of a siderophore takes place in stepwise processes, except the case of desferricrocin, with which, large-extent overlapping of the processes occurs. (iv) Out of the four tris-chelated [ML] type complexes, the complex of DFCR is the most compact, as it is indicated by the relaxivity values. (v) Following the stoichiometric oxidation of the Mn(II)-siderophore complexes at pH≥9, tris-chelated Mn(III) complexes are formed. To make a comparison between the stability of the Mn(III) and the corresponding Fe(III) complexes of DFCR and TAF, the determination of the stability of the Fe(III) complexes under our condition has also been performed, by using UV-Vis spectrophotometry. Comparable stability of the corresponding complexes was found. (vi) Correlation study of the stability constants resulted in estimation of the constant of the Mn(III) monohydroxo complex, for which there was no data in the literature under our conditions.

Relaxometric determination of binding between Mn(II)-UDP and Mn(II)-UDP-glucose in aqueous solution.

The applicability of relaxometry for the determination of formation constants of Mn(II)-UDP (logK=3.78) and Mn(II)-UDP-glucose (logK=2.98) complexes is demonstrated. The obtained value indicates a well-defined interaction between Mn(II) and UDP-glucose in aqueous solution (pH=5.50) with ΔG = -4.07 kcal/mol.

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.

Cavemen were better at depicting quadruped walking than modern artists: erroneous walking illustrations in the fine arts from prehistory to today.

The experts of animal locomotion well know the characteristics of quadruped walking since the pioneering work of Eadweard Muybridge in the 1880s. Most of the quadrupeds advance their legs in the same lateral sequence when walking, and only the timing of their supporting feet differ more or less. How did this scientific knowledge influence the correctness of quadruped walking depictions in the fine arts? Did the proportion of erroneous quadruped walking illustrations relative to their total number (i.e. error rate) decrease after Muybridge? How correctly have cavemen (upper palaeolithic Homo sapiens) illustrated the walking of their quadruped prey in prehistoric times? The aim of this work is to answer these questions. We have analyzed 1000 prehistoric and modern artistic quadruped walking depictions and determined whether they are correct or not in respect of the limb attitudes presented, assuming that the other aspects of depictions used to determine the animals gait are illustrated correctly. The error rate of modern pre-Muybridgean quadruped walking illustrations was 83.5%, much more than the error rate of 73.3% of mere chance. It decreased to 57.9% after 1887, that is in the post-Muybridgean period. Most surprisingly, the prehistoric quadruped walking depictions had the lowest error rate of 46.2%. All these differences were statistically significant. Thus, cavemen were more keenly aware of the slower motion of their prey animals and illustrated quadruped walking more precisely than later artists.

Interaction of folic acid and some matrix metalloproteinase (MMP) inhibitor folate-γ-hydroxamate derivatives with Zn(II) and human serum albumin.

Human serum albumin binding of folic acid and its γ-hydroxamate/carboxylate derivatives was studied by ultrafiltration and spectrofluorimetry, and it was found that the ligands exhibit a moderate binding (K(D) ~2-50 µM), and the folate-γ-phenylalanine represents the highest conditional binding constant towards albumin. This feature may have importance in the serum transport processes of these ligands. Interaction of folic acid and its derivatives with Zn(II) was investigated in aqueous solution to obtain the composition and stabilities of the complexes by the means of pH-potentiometry, (1)H NMR and electrospray ionization mass spectrometry, together with the characterization of the proton dissociation processes and the hydro-lipophilic properties of the ligands. The formation of mono-ligand complexes was demonstrated in all cases and the contribution of the glutamyl carboxylates to the coordination was excluded. Binding of folic acid and its γ-carboxylate derivatives to Zn(II) via the pteridine moiety is suggested, while the (O,O) coordination fashion of the folate-γ-hydroxamate ligands has importance in their inhibitory activity against Zn(II)-containing matrix metalloproteinases. It was found that the enzyme inhibition of these folate-γ-hydroxamate ligands is mainly tuned by other features, such as the lipophilic character rather than the Zn(II)-chelate stability.