Interaction between [(η--cym)M(HO)] (M = Ru, Os) or [(η-Cp*)M(HO)] (M = Rh, Ir) and Phosphonate Derivatives of Iminodiacetic Acid: A Solution Equilibrium and DFT Study.

The pH-dependent binding strengths and modes of the organometallic [(η--cym)M(HO)] (M = Ru, Os; -cym = 1-methyl-4-isopropylbenzene) or [(η-Cp*)M(HO)] (M = Rh, Ir; Cp* = pentamethylcyclopentadienyl anion) cations towards iminodiacetic acid (HIda) and its biorelevant mono- and diphosphonate derivatives N-(phosphonomethyl)-glycine (HIdaP) and iminodi(methylphosphonic acid) (HIda2P) 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 IdaP and Ida2P 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.

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, [(η--cym)Ru(HO)], and [(η-Cp*)Rh(HO)]-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.

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 (N,N) chelating sets (N = secondary amine; N = 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.

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.

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)](ClO), 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.

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))(quin)](ClO) or [(Co(4 N))(quinS)](ClO), where 4 N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa), quinH = quinizarin (1,4-dihydroxy-9,10-anthraquinone), quinSH = 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.

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, H and O-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, [(η--cym)Ru(HO)] as well as [(η-Cp*)Rh(HO)], 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.

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)](PF) (3) and [Co(tpa)(nor)(Co(tpa)(norH)](PF)(Cl)∙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.

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.

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 IC for both Cu-Ala-Phe (IC=4.

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.

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.

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.

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.

Suberoylanilide hydroxamic acid, a potent histone deacetylase inhibitor; its X-ray crystal structure and solid state and solution studies of its Zn(II), Ni(II), Cu(II) and Fe(III) complexes.

Reaction of the potent hydroxamate-based histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), with hydrated metal salts of Fe(III), Cu(II), Ni(II) and Zn(II) yielded a tris-hydroxamato complex in the case of Fe(III) and bis-hydroxamato complexes in the case of Cu(II), Ni(II) and Zn(II) both in the solid state and in solution. Reaction of the secondary hydroxamic acid, N-Me-SAHA, also yielded a tris-hydroxamato complex in the case of Fe(III) and bis-hydroxamato complexes in the case of Cu(II), Ni(II) and Zn(II) in solution. These metal complexes have the hydroxamato moiety coordinated in an O,O'-bidentate fashion.

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.

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.

Unsymmetrical dizinc complexes as models for the active sites of phosphohydrolases.

The unsymmetrical dinucleating ligand 2-(N-isopropyl-N-((2-pyridyl)methyl)aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)methyl)aminomethyl)-4-methylphenol (IPCPMP or L) has been synthesized to model the active site environment of dinuclear metallohydrolases. It has been isolated as the hexafluorophosphate salt H(4)IPCPMP(PF(6))(2) x 2 H(2)O (H(4)L), which has been structurally characterized, and has been used to form two different Zn(II) complexes, [{Zn(2)(IPCPMP)(OAc)}(2)][PF(6)](2) (2) and [{Zn(2)(IPCPMP)(Piv)}(2)][PF(6)](2) (3) (OAc = acetate; Piv = pivalate). The crystal structures of and show that they consist of tetranuclear complexes with very similar structures.

A bis(3-hydroxy-4-pyridinone)-EDTA derivative as a strong chelator for M3+ hard metal ions: complexation ability and selectivity.

The study of chelating compounds is very important to solve problems related to human metal overload. 3-Hydroxy-3-pyridinones (HP), namely deferiprone, have been clinically used for chelating therapy of Fe and Al over the last decade. A multi-disciplinary search for alternative molecules led us to develop poly-(3-hydroxy-4-pyridinones) to increase metal chelation efficacy.

Novel half-sandwich Ru(II)-hydroxamate complexes: synthesis, characterization and equilibrium study in aqueous solution.

Novel half-sandwich Ru(II)-benzohydroxamate complexes were synthesized. [Ru(eta(6)-p-cymene)(mu-bha)](2)Cl(2) (bhaH = benzohydroxamic acid) with (O,O) coordination of the ligand, was characterized by elemental analysis, spectroscopic ((1)H-NMR, IR) and ESI-MS methods. Replacement of the chloride of the precursor by CF(3)SO(3)(-) and reaction of the obtained [Ru(eta(6)-p-cym)(acetone)(3)](CF(3)SO(3))(2) with bhaH affords [Ru(eta(6)-p-cymene)(mu-bha)](2)(CF(3)SO(3))(2), the crystal and molecular structure of which has been determined by X-ray crystallography.

Combined chelation of bi-functional bis-hydroxypiridinone and mono-hydroxypiridinone: synthesis, solution and in vivo evaluation.

3-Hydroxy-4-pyridinones (3,4-HP) are well known iron-chelators with applications in medicinal chemistry, mainly associated with their high affinity towards trivalent hard metal ions (e.g. M(3+), M=Fe, Al, Ga) and use as decorporating agents in situations of metal accumulation.

Dihydroxamate based siderophore model, piperazine-1,4-bis-(N-methyl-acetohydroxamic acid (PIPDMAHA), as a chelating agent of molybdenum(VI).

Equilibrium studies based on pH-potentiometric and spectrophotometric measurements as well as some theoretical simulations are reported for the complexes of Mo(VI) with a dihydroxamate type siderophore analogue, the piperazine-1,4-bis-(N-methyl-acetohydroxamic acid) (PIPDMAHA). It has been found that the complexation process starts below pH 2 and that PIPDMAHA forms more stable O,O-hydroxamate bis-chelated complexes with Mo(VI) than any of the formerly studied dihydroxamic acids. The experimental data were fitted with two complexation models based either on dinuclear or on mononuclear species.

Structure-based differences between the metal ion selectivity of two siderophores desferrioxamine B (DFB) and desferricoprogen (DFC): why DFC is much better Pb(II) sequestering agent than DFB?

Complexation of desferrioxamine B (DFB) and desferricoprogen (DFC) with Cd(II) and Pb(II) toxic ions as well as complexation of DFC with Ca(II) and Mg(II) essential metals have been investigated and the results have been compared to those with other metal ions. The two siderophores have moderate Cd(II)-binding ability, but both, and especially DFC, bind Pb(II) in high stability complexes. Surprisingly, significant differences exist between Pb(II)-complexation of DFB and DFC.

New pyrazole-based ligands with two tripodal binding pockets: potential scaffolds for metallobiosite modeling.

The synthesis of a new set of bioinspired dinucleating ligand scaffolds HL1-HL3 based on a bridging pyrazolate with appended chelate arms is reported. The ligands provide two binding compartments akin to the tris(imidazolyl)methane motif, predisposed to act as facially tridentate coordination caps. Potentiometric titrations of HL1 in the presence of Ni2+ and Zn2+ reveal formation of species with a metal:ligand ratio 1:1 in aqueous solution, and UV-vis data for the NiII system suggest that the complex [L12Ni2]2+ with (NiN6) chromophore is formed under appropriate pH conditions.