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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.

The adverse side effects and acquired resistance associated with the clinical application of traditional platinum-based anticancer drugs have forced investigation of alternative transition metal-based compounds and their cytostatic properties. Over the last years, the anticancer potential of cobalt complexes has been extensively studied, and in-depth analyses of their mode of action have been conducted. In this work, we present antiproliferative activity against human cancer cells of the dinuclear Co(III) complexes bearing the quinizarin ligand and tris(2-aminoethyl)amine (tren, compound 1) or tris(2-pyridylmethyl)amine (tpa, compound 2) co-ligands. To contribute the understanding mechanisms of biological action of these compounds, their association with DNA in the cells, DNA binding in cell-free media, and DNA cleavage capability were investigated in detail. The results demonstrate that both complexes interact with DNA in tumor cells. However, their mechanism of antiproliferative action is different, and this difference is mirrored by distinct antiproliferative activity. The antiproliferative effect of 1 is connected with its ability to intercalate into DNA and subsequently to inhibit activities of DNA processing enzymes. In contrast, the total antiproliferative efficiency of 2, thanks to its redox properties, appears to be connected with its ability to form radicals and, consequently, with the ability of 2 to cleave DNA. Hence, the findings presented in this study may significantly contribute to understanding the antitumor potential of cobalt complexes. Dinuclear Co(III) complexes containing the bioactive quinizarin ligand exhibit antiproliferative activity based on distinct mechanism.

The X-ray crystal structure and pKa values of GSK322, a well-known and effective peptide deformylase inhibitor and antibacterial drug candidate, are reported. The first examples of Co(iii) complexes of N-formyl hydroxylamines are reported. Reaction of N-hydroxy-N-phenylformamide (HFA) with [Co(tren)Cl2]Cl and [Co(tpa)Cl2]Cl (where tren = tris(2-aminoethyl)amine, tpa = tris(2-pyridylmethyl)amine) with one equivalent of NaOH in H2O afforded [Co(tren)(HFA-1H)](PF6)1.5Cl0.5 (1) and [Co(tpa)(HFA-1H)]Cl2 (2), respectively. X-ray crystal structures of both complexes revealed that the N-formyl hydroxylamine group acts as a bidentate ligand, coordinating the Co(iii) centres via the carbonyl oxygen and deprotonated hydroxy group (O,O'), a coordination mode typically observed for closely related mono-deprotonated hydroxamic acids. Reaction of the N-formyl hydroxylamine-based GSK322 with [Co(tpa)Cl2]Cl afforded the corresponding Co(iii) chaperone complex of the peptide deformylase inhibitor, [Co(tpa)(GSK322-1H)](PF6)2. GSK322 and [Co(tpa)(GSK322-1H)](PF6)2 exhibited better Gram-positive activity than Gram-negative, where low MICs (1.56-6.25 μM) were determined for S. aureus strains, independent of their antibiotic susceptibility.

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: (1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; (2) the biological effect was influenced by the nature of the central azole ring of the ligands—1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; (3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin’s lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

The interaction with red blood cells (RBC) of vanadium(V) complexes formed by 3,5-difluoropicolinic acid (HpicFF), 3-hydroxypicolinic acid (H2hypic) and pyrazinecarboxylic acid (Hprz) has been examined. Electron Paramagnetic Resonance (EPR) spectroscopy results suggest that V(V) is reduced in all cases to V(IV) inside the erythrocytes. The thermodynamic stability of V(V) and corresponding V(IV) complexes has been related with the species detected in the cellular environment; when the ligands form unstable complexes with both VVO2+ and VIVO2+ ions (picFF and prz), the species formed inside RBC are similar to those observed when starting with vanadate(V) alone, that is VIVO2+ –formed upon V(V) reduction– distributing among the cellular bioligands forming different types of complexes. When in the ligand molecule other groups able to form chelated complexes are present (hypic), more stable species are formed inside the RBC. The amount of complex able to enter the RBC depends on the ligand structure which could influence the metal uptake. The interaction of different VIVO2+ complexes formed by picolinate (picFF, pic = picolinate, picCN = 5-cyanopicolinate) and pyrazinecarboxylate (prz and przNH2 = 3-aminopyrazine-2-carboxylate) derivatives with hemoglobin (Hb), which is the main candidate to bind the VIVO2+ ion in the cytosol, was also investigated to rationalize the results. The ligands which form at physiological pH relatively stable complexes with VIVO2+ (przNH2 and pic) can give inside the erythrocytes mixed species after the replacement of an equatorial water molecule by an imidazole nitrogen of a histidine residue of the protein, while the ligands which form with VIVO2+ unstable complexes (picCN, picFF, prz) yield the same species observed in the binary system VIVO2+–Hb.

GANT61-D is an important hedgehog pathway inhibitor and an interesting ligand candidate for metal coordination. The first examples of metal complexes of the potent hedgehog pathway inhibitor GANT61-D are described. The reaction of Ni(II), Pd(II), and Pt(II) precursors with the hedgehog pathway inhibitor GANT61-D gave [NiII(GANT61-D)(OH2)3(μ2-SO4)(μ3-SO4)] (1), [PdII(Cl)(GANT61-D)]Cl (2), [PtII(Cl)(GANT61-D)]Cl, and [PtII(CBDCA-2H)(GANT61-D)]. X-ray crystal structure analysis revealed that GANT61-D is a versatile N-donor ligand that can act as a bidentate ligand via the diaminopropane (DAP) N atoms or a tridentate ligand via the DAP N atoms and one dimethylaniline N atom. Protonation constants of the GANT61-D ligand in water and in a 60:40 (w/w) dimethyl sulfoxide-water solvent mixture were determined. Potentiometric and spectroscopic data on the NiII(GANT61-D) system indicate the formation of octahedral 1:1 species with medium stability in solution. 1 and 2 exhibited noteworthy in vitro cytotoxicity against medulloblastoma cancer cells.

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.

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.

Primary and secondary di- and tripeptide hydroxamic acids, Ala-Ala-NHOH, Ala-Ala-N(Me)OH, Ala-Gly-Gly-NHOH and Ala-Gly-Gly-N(Me)OH were synthesized and their interaction with Pd(II) (as a Pt(II) model but with faster ligand exchange reactions) was studied in aqueous solution in the presence of the Cl− competitor ion by pH-potentiometric and 1H NMR methods. To the best of our knowledge, this is the first detailed solution study on Pd(II)–peptide hydroxamate systems revealing that, except for Ala-Gly-Gly-NHOH, the other three ligands act not only as coordination compounds, but also the hydrolysis of the coordinated ligands and formation of the protonated hydroxylamine and Pd(II) complexes of the corresponding peptides under acidic conditions occurred. The hydrolysis was rather slow with Ala-Gly-Gly-N(Me)OH (more than one week), and just a bit faster with Ala-Ala-NHOH, so speciation studies could also be performed successfully on the systems containing one of the latter two ligands. This was, however, hindered for the Pd(II)–Ala-Ala-N(Me)OH system, where, in addition to the quite fast hydrolysis of the ligand, the reduction of Pd(II) to elementary metal by the N(Me)-hydroxylamine formed was also observed. Speciation studies with Ala-Gly-Gly-NHOH revealed the predominance of a very stable 4N-donor complex, (NH2, 2Namide, Nhydr.) over a wide pH range. This ligand is also capable of binding the metal ion excess with the hydroxymate (O,O) set in dinuclear species. The formation of this latter type of complex is hindered with the secondary analogue, Ala-Gly-Gly-N(Me)OH, where, in addition to the 3N donor atoms, the hydroxamate-O is also involved in the coordination of the most stable complex. However, the formation of mixed hydroxo species at high pH and a bis-complex in a rather slow process with (NH2, Namide)2 bonding mode in the presence of ligand excess was proven. Although the 3N coordination (NH2, Namide, Nhydx) results in a highly stable complex with the dipeptide derivative, Ala-Ala-NHOH, the fourth coordination site remains free for accepting an NH2 moiety from the excess ligand, or a hydroxide ion at high pH. Likewise, the hydroxymate (O,O) set remains free to bind the metal ion excess in a trinuclear species. The results of this study may also contribute to the design and synthesis of novel Pt(II) complexes with anticancer potential.

Copper(II), nickel(II), zinc(II) and organometallic ruthenium(II) ([(η6-p-cym)Ru(H2O)3]2+) complexes of an N-terminally free heptapeptide containing four histidyl residues (NH2-HAVAHHH-NH2) have been studied by potentiometric and various spectroscopic techniques (UV-vis, CD, NMR and ESI-MS). The data revealed a significant selectivity in the metal binding ability of this ligand. Histamine-like coordination of the amino terminus is the primary binding mode for all metal ions but the internal histidyl residues can also contribute to the overall stability of the complexes. Copper(II) and nickel(II) ions are able to induce the deprotonation and coordination of the amide functions both at the amino terminus and around the internal histidyl sites, resulting in the co-existence of various coordination isomers or the formation of dinuclear complexes in the presence of excess of metal ions.

Aims: The aim of the present study was to investigate the biochemical properties of nitrosopersulfide (SSNO -), a key intermediate of the nitric oxide (NO)/sulfide cross talk. Results: We obtained corroborating evidence that SSNO - is indeed a major product of the reaction of S-nitrosothiols with hydrogen sulfide (H 2S). It was found to be relatively stable (t 1/2 *1 h at room temperature) in aqueous solution of physiological pH, stabilized by the presence of excess sulfide and resistant toward reduction by other thiols. Furthermore, we here show that SSNO - escapes the reducing power of the NADPH-driven biological reducing machineries, the thioredoxin and glutathione reductase systems. The slow decomposition of SSNO - produces inorganic polysulfide species, which effectively induce per/polysulfidation on glutathione or protein cysteine (Cys) residues. Our data also demonstrate that, in contrast to the transient activation by inorganic polysulfides, SSNO - induces long-term potentiation of TRPA1 (transient receptor potential ankyrin 1) channels, which may be due to its propensity to generate a slow flux of polysulfide in situ. Innovation: The characterized properties of SSNO - would seem to represent unique features in cell signaling by enabling sulfur and nitrogen trafficking within the reducing environment of the cytosol, with targeted release of both NO and polysulfide equivalents. Conclusion: SSNO - is a surprisingly stable bioactive product of the chemical interaction of S-nitrosothiol species and H 2S that is resistant to reduction by the thioredoxin and glutathione systems. As well as generating NO, it releases inorganic polysulfides, enabling transfer of sulfane sulfur species to peptide/protein Cys residues. The sustained activation of TRPA1 channels by SSNO - is most likely linked to all these properties. Antioxid. Redox Signal. 33, 1277–1294.

Fourteen novel CoIII ternary complexes with the general formula [Co(4 N)(2O)]X2 or [Co(2 N)2(2O)]X2 where 4 N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa); 2 N = 1,10-phenantroline (phen), 2,2′-bipyridine (bipy), 1,2-diaminoethane (en) or 2-(aminomethyl)pyridine (ampy) and 2O = 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone (dhpH), 3-hydroxy-2-methyl-4-pyrone (maltH) or 2-ethyl-3-hydroxy-4H-pyran-4-one (etmaltH) were synthesized, characterized and their redox features explored. Molecular structure of some selected [Co(2 N)2(2O)](ClO4)2 (2 N = phen, bipy, en; 2O = dhp, malt) or [Co(4 N)(2O)](ClO4)2 (4 N = tpa; 2O = etmalt) type complexes were assessed by X-ray diffraction and showed the expected octahedral geometry. Replacement of the 4 N donor ligands by two 2 N donor ligands resulted in the decrease of the cathodic peak potential of the complexes indicating easier reduction and allowing therefore the tailoring of the redox properties of the complexes. Screening of selected compounds against a human derived cancer cell line, HeLa, showed that, unlike the [Co(4 N)(2O)]X2 derivatives, the complexes containing 2 N = bipy or phen ligands have better anticancer activity than cisplatin or carboplatin.

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.

A novel peptide conjugate (H(L2)) incorporating N-donors of the peptide backbone and an (O,O) donor set of a hydroxypyridinone moiety is synthesized and characterized. This ambidentate chelating ligand is intended to develop Co(III)/Pt(II) heterobimetallic multitargeted complexes with anticancer potential. To explore its metal ion binding ability the interaction with Pd(II) (as a Pt(II) model but with faster ligand exchange reactions) was studied in aqueous solution by the combined use of pH-potentiometry, NMR and HR MS. In an equimolar solution H(L2) was found to bind Pd(II) via the terminal amino group and increasing number of peptide nitrogens of the peptide backbone over a wide pH range. Around physiological pH an (N,N) and (O,O) chelated 2 : 2 minor species was also identified. At a 2 : 1 Pd(II) to ligand ratio the formation of dinuclear species, [Pd2H–x(L2)] (x = 1–4), with high stability and with the involvement of the (O,O) chelating set of the ligand too, was demonstrated. Reaction of H3(L2)2+ with Pd(II) in the presence of chloride ions at pH ∼ 2.0 afforded [PdH(L2)Cl2]·2H2O (3) in a solid state whose molecular structure was assessed by single crystal X-ray diffraction. The structure of 3 revealed that Pd(II) is coordinated by a (NH2, Namide) chelate of the ligand in a square planar fashion. It also indicates that under suitable conditions a 2N coordinated Pd(II) complex can also be obtained even in the presence of four available nitrogen donors in the chelatable position in the ligand most likely due to its neutral charge and the decreased conditional stability of the amide-involved chelate(s) under acidic conditions. Reaction of H(L2) with [Co(tren)]3+ (tren = tris(2-aminoethyl)amine) revealed the exclusive coordination of (L2)−via its (O,O) chelate to the metal core while treatment of the Co-complex with Pd(II) resulted in the formation of a Co/Pd heterobimetallic complex in solution with (NH2, Namide) chelated Pd(II). Reaction of 3 with 9-methylguanine indicated the N7 coordination of this simple DNA model to Pd(II) in a 1 : 1 ratio.

Complexation of deferasirox (4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid, H3LB) and its decarboxy derivative (H2LA) with Ru(III), Os(IV), Co(III) and Ga(III) was studied. These novel complexes with likely multitargeted capabilities are expected to show anticancer potential after biotransformation via both of the metal ion and the liberated ligand. Formation of 1:2 octahedral complexes with a (O,N,O) tridentate coordination of the ligands was found yielding K3[Ru(LB)2], K[Co(LA)2], K3[Co(LB)2] and (guanidinium)Na2[Ga(LB)2], respectively. The molecular structure obtained by single crystal X-ray diffraction also confirmed the octahedral geometry for K[Co(LA)2]∙2PriOH. Unprecedented formation of K2[OsVILB(O)2(OH)] having a tridentate (O,N,O) coordinating ligand, two oxo groups and a hydroxide ion in the coordination sphere of the metal ion with + 6 oxidation state was also found. Simple synthesis and solid state structure of the novel disulfonated derivatives of H3LB, and H2LA, (H5LD and H4LC, respectively, with excellent water solubility) is also presented. Interaction of Ga(III) with H4LD− and H3LC− resulted in the formation of 1:1 and 1:2 complexes with different protonation degree in aqueous solution among them [Ga(LD)2]7− and [Ga(LC)2]5− being the major species under physiologically relevant conditions.

The adverse side effects and acquired resistance associated with the clinical application of traditional platinum-based anticancer drugs have forced investigation of alternative transition metal-based compounds and their cytostatic properties. Over the last years, the anticancer potential of cobalt complexes has been extensively studied, and in-depth analyses of their mode of action have been conducted. In this work, we present antiproliferative activity against human cancer cells of the dinuclear Co(III) complexes bearing the quinizarin ligand and tris(2-aminoethyl)amine (tren, compound 1) or tris(2-pyridylmethyl)amine (tpa, compound 2) co-ligands. To contribute the understanding mechanisms of biological action of these compounds, their association with DNA in the cells, DNA binding in cell-free media, and DNA cleavage capability were investigated in detail. The results demonstrate that both complexes interact with DNA in tumor cells. However, their mechanism of antiproliferative action is different, and this difference is mirrored by distinct antiproliferative activity. The antiproliferative effect of 1 is connected with its ability to intercalate into DNA and subsequently to inhibit activities of DNA processing enzymes. In contrast, the total antiproliferative efficiency of 2, thanks to its redox properties, appears to be connected with its ability to form radicals and, consequently, with the ability of 2 to cleave DNA. Hence, the findings presented in this study may significantly contribute to understanding the antitumor potential of cobalt complexes. Dinuclear Co(III) complexes containing the bioactive quinizarin ligand exhibit antiproliferative activity based on distinct mechanism.

Sixteen cobalt(III) complexes incorporating one of the investigated 4N donor tripodal amines in the presence or absence of differently substituted hydroxamates have been synthesized and the effect of the nature of the N-donor, size of the chelates formed and the effect of the type of the substituent(s) at the hydroxamate moiety on the redox properties of the complexes have been studied. The crystal and molecular structures of the new complexes, [Co(uns-penp)(H 2 O)Cl]Cl 2 ·H 2 O ( 4 ), [Co(tren)(phebha)](ClO 4 ) 2 ( 11 ), [Co(tpa)(bha)](ClO 4 ) 2 ·C 2 H 5 OH·H 2 O ( 15 ) and [Co(tpa)(phebha)](ClO 4 ) 2 ( 16 ) have also been determined by single crystal X-ray diffraction method. Cyclic voltammetric (CV) results indicated the irreversible reduction of Co(III) in all the investigated complexes. Out of the four studied tripodal amines, abap was found to decrease the Co(III/II) reduction potential far below the region of bioreductants. Decreasing of two of the chains by one CH 2 in tren compared to abap resulted in less negative reduction potential of the corresponding complex. Further positive shift was observed by introducing two (uns-penp), and especially three (tpa) π-back-bonding pyridyl rings into the chains of tetramines. In agreement with literature results, the 3+ oxidation state of the central cobalt ion was found to be extremely stabilized in the ternary complexes containing the doubly deprotonated benzohydroximate, but the metal ion is significantly more reducible in the ternary complexes with mono-deprotonated benzohydroxamate/derivative ligands. Measurable effect was not found on the redox potential via introduction of chloro or nitro substituents in para position into the phenyl moiety of bha − (Cl-bha − and NO 2 -bha − ). Significant positive shift (ca. 200 mV) was obtained, however, when R N = H was replaced by a phenyl ring in phebha − therefore complexes with this latter ligand can be likely candidates for the in vitro releasing of hydroxamates with proven biological activity.

Quinolone derivatives are among the most commonly prescribed antibacterials in the world and could also attract interest as organic ligands in the design of metal complexes with potential pharmacological activity. In this study, five compounds, belonging to the first (nalidixic acid or Hnal), second (ciprofloxacin or Hcip, and norfloxacin or Hnor) and third generation (levofloxacin or Hlev, and sparfloxacin or Hspar) of quinolones, were used as ligands to bind the VIVO2+ ion. In aqueous solution, mono- and bis-chelated species were formed as a function of pH, with cis-[VOHxL2(H2O)]x+ and [VOHxL2]x+, x = 0-2, being the major complexes at pH 7.4. DFT calculations indicate that the most stable isomers are the octahedral OC-6-32 and the square pyramidal SPY-5-12, in equilibrium with each other. To the best of our knowledge, this is the first case that an equilibrium between a penta-coordinated square pyramidal complex and a hexa-coordinated octahedral complex is observed in solution for ligands forming six-membered chelated rings. Nalidixic acid forms the solid compound [VO(nal)2(H2O)], to which a cis-octahedral geometry was assigned. The interaction with 1-methylimidazole (MeIm) causes a shift of the equilibrium SPY-5 + H2O ? OC-6 toward the right after the formation of cis-[VOHxL2(MeIm)]x+, where MeIm replaces an equatorial water ligand. The study of the systems containing [VO(nal)2(H2O)] and the serum proteins - albumin (HSA), apo-transferrin (apo-hTf) and holo-transferrin (holo-hTf) - indicates that HSA and holo-hTf form the mixed species {VO(nal)2}y(HSA) and {VO(nal)2}y(holo-hTf), where y = 1-3 denotes the number of VO(nal)2 moieties bound to accessible histidines (His105, His367, His510 for HSA, and His25, His349, His606 for holo-hTf), whereas apo-hTf yields VO(nal)2(apo-hTf) with the coordination of the His289 residue only. Docking calculations suggest that the specific conformation of apo-hTf and the steric hindrance of the cis-VO(nal)2 moiety interfere with its interaction with all the surface His residues and the formation of a hydrogen bond network which could stabilize the binding sites.

Complexation of the secondary N-methyl-acetohydroxamic acid (HMeaha) with [(eta(6)-p-cym)Ru(H2O)(3)](2+), [(eta(5)-Cp*)Rh(H2O)(3)](2+), [(eta(6)-p-cym)Os(H2O)(3)](2+) or [(eta(5)-Cp*)Ir(H2O)(3)](2+) cations and the primary acetohydroxamic acid (HAha) with the former two cations (first time in the literature) has been studied in aqueous solution using pH-potentiometry, NMR, ESI-MS and DFT calculations. Because the arene or arenyl ligands take three coordination sites of the metal ion, only three remain free for interaction with additional ligand(s). Meaha(-) forms five-membered hydroxamate type chelated [ML](+) and [M(OH)L], being the third coordination site occupied by a water molecule in the former complex and by a hydroxide ion in the latter one. While [ML](+) remains predominant even under basic conditions in the Ru- and Rh-containing systems, it is measurable only in slightly acidic region with the two 5d metal ions. Also the tendency for hydrolysis of the aqua ligand in [ML(H2O)](+) complexes follows the trend of the cations for hydrolysis, Os > Ir > Ru > Rh. The X-ray result did not show any role of the H substituent of Aha(-) in [{(eta(5)-Cp*)Rh}(2)((2)-Aha)(2)](2+), in solution, however, its significant role was supported especially with Ru. All the results support the formation of a stable trinuclear [M3H-2L3(H2O)](+) species in which doubly deprotonated (hydroxymate type) ligands bridge two metal centres by coordinating via the two oxygens to the one cation and via the N-donor to another one.

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 muM, [VO(Me2phen)(citrH-1)]2- and VO-Me2phen-Protein are the major species, while for concentrations lower than 10 muM, (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.

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.

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&mdash, AlaAlaNHOH, AlaAlaN(Me)OH, AlaGlyGlyNHOH, and AlaGlyGlyN(Me)OH&mdash, with 4d metals: the essential Mo(VI) and two half-sandwich type cations, [(&eta, 6-p-cym)Ru(H2O)3]2+ as well as [(&eta, 5-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.

The interaction with erythrocytes of four [V(V)O2L2]- complexes, with L = picolinate (pic), 5-cyanopicolinate (picCN), 3-aminopyrazine-2-carboxylate (przNH2), and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp), was studied. The thermodynamic stability at physiological pH is: [V(V)O2(dhp)2]- > [V(V)O2(przNH2)2]- > [V(V)O2(pic)2]- > [V(V)O2(picCN)2]-. With picCN and pic, V exists at physiological pH as H2V(V)O4-, with przNH2 as a mixture of H2V(V)O4- and [V(V)O2(przNH2)2]- and with dhp as [V(V)O2(dhp)2]-. In the systems with pic and picCN, H2V(V)O4- and the ligands cross the erythrocyte membrane independently, with dhp the uptake occurs by diffusion, whereas with przNH2 both the mechanisms are active. Inside erythrocytes stable V(IV)OL2 complexes are formed, indicating that there is no relationship with the stability and redox state of the administered compounds and that, if the metal ion changes its oxidation state in the cytosol as V does, unstable complexes in the extracellular medium could become stable inside the cells and contribute to the pharmacological action.

Novel, dipeptide hydroxamic acids, L-Ala-L-AlaN(Me)OH and L-Ala-L-SerN(Me)OH, as well as the corresponding Z-protected ones, Z-L-Ala-L-AlaN(Me)OH and Z-L-Ala-L-SerN(Me)OH (Z = benzyloxycarbonyl) were synthesized and the metal ion binding capabilities toward Fe(III), Al(III), Ni(II), Cu(II) and Zn(II) were studied by combined pH-potentiometric and spectroscopic (UV–VIS, EPR) methods in aqueous solution. Each of these derivatives contains a methyl substituent at the hydroxamate N making it unsuitable for metal ion coordination. By making a comparison of the obtained results with our previously published ones for the corresponding primary hydroxamates, the effects of the replacement of hydroxamic-NH (primary) by hydroxamic-N(Me) (secondary) and that of the protection at the N terminus of the peptide chain (Z-protected ligands) on the metal binding capability as well as metal ion selectivity are evaluated in this paper. Except the significantly decreased solubility of their complexes, the Z-protected derivatives can coordinate as the simple analogous monohydroxamates. Fe(III) and Al(III) with hard character were found to form [O, O] chelated hydroxamate species with all the ligands studied. Like the corresponding primary ligands secondary derivatives were found to form [O, O] and [NH2, CO] chelated linkage isomers with Zn(II). For Ni(II) the deprotonation and coordination of the amide group is disfavoured when the hydroxamate N as binding site is blocked. Unlike primary dipeptide hydroxamates, the secondary ones, in their most stable complex, coordinate to Cu(II) via an [NH2, Namide, Ohydrox.] chelate and the formation of oligonuclear complexes, as it was shown previously with the corresponding primary analogues, cannot be detected. No indication was found for the role of the hydroxyl group of the serine moiety in metal ion binding. The results show that, unlike for the M(III) metal ions, in the case of M(II) ones there is a preference of complexation with the primary derivatives over the secondary ligands. This preference was found to be the most pronounced for Cu(II).

Complex formation between [Pd(en/pic)(H2O)2]2+ (en = ethylenediamine, pic = pyridine-2-methylamine) and primary hydroxamic acids (ahaH = acetohydroxamic, bhaH = benzohydroxamic acid) or secondary hydroxamic acids (meahaH = N-methyl-acetohydroxamic, pheahaH = N-phenylacetohydroxamic and phebhaH = N-phenylbenzohydroxamic acid) was studied in aqueous solution by pH-potentiometry, 1H NMR and ESI-TOF-MS. Secondary hydroxamates form 1:1 species with the [Pd(N,N)(H2O)2]2+ ions via the [O,O] chelating sets. Unexpectedly, in the primary ligands deprotonation and coordination of the hydroxamate-NH starts as low as pH

A novel ambidentate type hydroxamic acid derivative (phenhaH, 1) containing an (O,O) and a 1,10-phenantroline (phen) based (N,N) donoratom set together with its heterobimetallic complexes incorporating an octahedral [Co(4 N)]3+ (4 N = tris(2-aminoethyl)amine (tren) or tris(2-methylpyridyl)amine (tpa)) and a half-sandwich type [(η6-p-cym)Ru]2+ entity have been synthesized and characterized using various analytical techniques. Reaction of [Co(4 N)Cl]Cl2 with 1 proved the exclusive (O,O) coordination of the ligand to the [Co(4 N)]3+ core to yield [Co(tpa)(phenha)](ClO4)2, (2). Subsequent treatment of 1 with [Ru(η6-p-cym)Cl2]2 and [Co(4 N)Cl]Cl2 in a one-pot reaction resulted in the formation of [(η6-p-cym)Ru(Cl)(phenha)Co(tren)]Cl(PF6)2 (3) and [(η6-p-cym)Ru(Cl)(phenha)Co(tpa)](PF6)3 (4) in which the organometallic Ru core is coordinated by the phen part while the Co entity by the hydroxamate part of 1. Cyclic voltammetry revealed that 4 could be reduced at a less negative potential and exhibits a reversible Co(III)/Co(II) redox process compared to 3 due to the π-back bonding interaction between the Co(III) centre and the pyridyl-N donors of tpa in 4. Complexes 2–4 were tested for their in vitro cytotoxicity using human-derived cancer cell lines (HeLa, MCF-7, HCT116 and MDA-MB-231) and showed moderate anti-proliferative activity in the double digit micromolar concentration range, 4 being the most active. Complex 4 displayed better activity against MDA-MB-231 cells than cisplatin.

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.

Quinolone derivatives are among the most commonly prescribed antibacterials in the world and could also attract interest as organic ligands in the design of metal complexes with potential pharmacological activity. In this study, five compounds, belonging to the first (nalidixic acid or Hnal), second (ciprofloxacin or Hcip, and norfloxacin or Hnor) and third generation (levofloxacin or Hlev, and sparfloxacin or Hspar) of quinolones, were used as ligands to bind the V

In this work the speciation in aqueous solution of the compound [V IV O(oda)(H 2 O) 2 ], where oda is oxydiacetate dianion (OOCCH 2 ) 2 O, which shows in vitro anticancer activity, was studied. Its interaction with the two serum bioligands with highest affinity for V IV , lactic (Hlact) and citric (H 3 citr) acid, and with the two proteins candidate to participate to the transport of V IV O compounds in the organism, transferrin (hTf) and albumin (HSA), was also examined. The study was carried out with the combined application of spectroscopic (Electron Paramagnetic Resonance, EPR), analytical (pH-potentiometry) and computational (Density Functional Theory, DFT) methods. The results showed that in aqueous solution [VO(oda)(H 2 O) 2 ] undergoes hydrolysis above pH 4–5 with formation of the EPR-active species [(VO) 2 (oda) 2 (OH) 2 ] 2− around pH 6 and of [(VO) 2 (OH) 5 ] − at physiological pH. DFT calculations suggested that the most stable isomers of 1:1 species are the hexa-coordinated OC -6-23 with a mer arrangement of oda – similar to that observed in the solid state – and the penta-coordinated SPY -5-14, whereas for 1:2 species the fac arrangement of oda is favored. Citrate is able to displace completely the oda ligand in [VO(oda)(H 2 O) 2 ] and only the dinuclear species [(VO) 2 (citrH -1 ) 2 ] 4− was detected at pH 7.4, while with lactate the formation of a mixed complex V IV O–oda–lact was observed. [VO(oda)(H 2 O) 2 ] interacts with apo-transferrin forming a mixed complex (VO)(hTf)(oda) where vanadium is bound in the iron sites and oda behaves as a synergistic anion, while with albumin no interaction was revealed. Model calculations suggest that when [VO(oda)(H 2 O) 2 ] is administered orally (concentration ca . 1–10 μM) or by injection (concentration approximately in the range 10–100 μM), (VO)(hTf) and (VO) 2 (hTf) should be formed; these species could reach the target organs and be recognized by the hTf receptors of the cells, favoring the vanadium uptake.

Complex formation equilibria between [(η5-Cp*)RhIII(H2O)3]2+ and aminohydroxamic acids (L-2-amino-N-hydroxyacetamide (α-alahaH), 3-amino-N-hydroxypropanamide (β-alahaH) and 4-amino-N-hydroxybutanamide (GABAha, γ-abhaH)) having the primary amino group in different chelatable positions relative to the hydroxamic function were studied using pH-potentiometric, 1H NMR and ESI-MS methods and the formation constants of the complexes present in aqueous solution are reported. The relative order of the pH-dependent conditional stability of the hydroxamate type (O,O) and (Namino,Nhydroxamato) chelates was found to determine to a great extent the coordination modes both in the mono- and various dinuclear species formed. While with α-alaha−, a 5-membered (N,N) chelated mononuclear complex predominates, with β-alaha− in a wide pH-range, very stable dinuclear cluster ions exist. With γ-abha−, in the most stable complexes, two ligands (in reverse variation) link two half-sandwich cations, coordinating each ligand via the hydroxamate chelate to one metal centre, while via the amino-N to the other one. This arrangement seems to be further stabilized by a hydrogen bond as DFT calculations support the extra stabilization effect of internal H-bonding in [{(η5-Cp*)RhIII}2H−1(γ-abha)2]+. The synthesis, spectral (NMR and IR) and MS characterization of a novel complex with an iridium analogue, [(η5-Cp*)IrIII(α-alaha)Br] (1) is also described. This complex was tested for its in vitro cytotoxicity using human-derived cancer cell lines (A2780, HeLa, DU-145, A549, and MCF-7) and showed insignificant anti-proliferative activity in the micromolar concentration range.

Solution equilibrium study on Pb(II) complexes of 3-hydroxy-2-methyl-4-pyrone (maltol, maltH) and its two derivatives, 3-hydroxy-2-methyl-4 H -pyran-4-thione (thiomaltol, thiomalH) and 3-hydroxy-1,2-dimethyl-4-pyridinone (dhpH) have been performed by using pH-potentiometry, 1 H NMR, ESI MS methods. Out of the studied ligands, the (S,O)-chelating thiomalt was found to form the most stable mono- and bis-chelated type species, [PbL] + and [PbL 2 ], but limited water solubility hindered the examination on this system above pH 7. The Pb(II)-binding capabilities of malt and especially dhp are still very good and the higher extent of electron delocalization in dhp compared to malt results not only in the increased stability of the 5-membered (O,O) dhp chelate, but also the possibility of some involvement of the 6s 2 lone electron pair of Pb(II) in the bonding. Furthermore, dhp, compared to malt, is not just a more effective Pb(II) chelator, but also shows better selectivity toward Pb(II) against Zn(II).

[(η6-p-cym)Ru(H2O)3]2+ binding strength of the thioether ligands DL-methionine (H2met+) or S-methyl-L-cysteine (H2mecys+) was studied with the combined use of pH-potentiometry, NMR and mass spectrometry in aqueous solution. Both ligands were found to form stable [(η6-p-cym)RuA]+ complexes with [S, NH2, COO−] coordination of the amino acids over a wide pH-range. A log βRuA value of 17.2(2) was obtained from NMR titrations for the met system by a competition reaction with hydroxide ions. Comparison of the [(η6-p-cym)Ru(H2O)3]2+ binding strength of the [O, O, O] (citrate), [O, N, O] (isoserine) and [S, N, O] (met) donor sets at pH = 7.4 reveals the exclusive formation of a [S, N, O] chelated metal complex. Synthesis and characterisation of [(η6-p-cym)Ru(L)]X, [(η6-p-cym)Os(L)]Cl or [(η5-Cp*)M′(L)]Cl (L = mecys, DL-met, L-met; X = Cl, NO3, CF3SO3; M′ = Rh, Ir) complexes together with the molecular structures of the [(η6-p-cym)Ru(mecys)]NO3 (10) and [(η6-p-cym)Ru(met)]NO3 (11) obtained by the X-ray diffraction method are reported. Both tridentate ligands form chiral-at-metal complexes in which the configuration of the metal centre is determined by the ligands containing a stereogenic centre (αC) as well. Diffraction data indicate that 10 contains the RRuRαCSS stereoisomer while 11 consists of the RRuSαCRS and SRuRαCSS enantiomers in the lattice. Owing to the labile configuration of the thioether sulfurs epimerisation in both systems was detected and the ratio of the diastereomers was estimated. 11 together with [(η6-p-cym)Ru(L-met)]Cl (3), [(η5-Cp*)Rh(DL-met)]Cl (7) and [(η5-Cp*)Ir(DL-met)]Cl (9) were tested for their in vitro cytotoxicity using human-derived ovarian cancer lines (A2780) and showed no anti-proliferative activity in the concentration range (0–50 μM) studied.

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.

The interactions between [(η6-p-cymene)Ru(H2O)3]2+ and L-malic acid (H2mal), L-tartaric acid (H2tart), and their sulfur-containing analogues dl-thiomalic acid (H3thiomal) and meso-2,3-dimercaptosuccinic acid (H4dmsa) were studied by pH potentiometry, NMR spectroscopy, and ESI-MS. The hydroxycarboxylates are potent metal ion binders and prevent hydrolysis at pH 7.4 in aqueous solution. Although H2mal forms mononuclear complexes with different degrees of protonation by the involvement of the alcohol/alkoxide group in addition to the carboxylate groups, the presence of binding isomers is detected for the H2tart system. The replacement of the alcohol group by a thiolate group results in the formation of dinuclear [Ru2A2] complexes as the single species over a wide pH range. Complexes with identical binding modes with H3thiomal or polymeric species with H4dmsa are identified, and the X-ray structure of [{(η6-p-cym)Ru}2(Hthiomal)2] is reported. The stereochemistry of the chiral-at-metal complexes was explored by NMR spectroscopy and is also discussed.

Hydrolysis of half-sandwich-type platinum metal cations with the general formula [M(η6-arene)(H2O)3]2+ {M = Ru, Os; η6-arene = benzene, toluene, 1-methyl-4-isopropylbenzene (p-cym), or 1,3,5-triisopropylbenzene (tri-iPr)} or [Ir(η5-Cp*)(H2O)3]2+ (Cp* = pentamethylcyclopentadienyl anion) was studied in aqueous solution in the presence of 0.20 M KNO3 or KCl as a background electrolyte to explore the effects of the type of metal ion, the moderately coordinating monodentate chloride ion, and the electron-donating ability of the arene ligand. Replacement of Ru by Os enhances the formation of the biologically less-active, triple hydroxido-bridged dimer, [{M(η6-arene)}2(μ2-OH)3]+, whereas in the presence of Cl– complete hydrolysis is suppressed owing to the formation of various chlorido and mixed chlorido/hydroxido species as intermediates. A linear relationship was found between the stability constants of the [{Ru(η6-arene)}2(μ2-OH)3]+ complexes in the presence of arenes with different electron-donating abilities and various atomic and molecular parameters of the corresponding [Ru(η6-arene)(H2O)3]2+ cations; the triisopropylbenzene derivative was the most resistant to hydrolysis. The results of this study may help in rationalizing the bioactivity of anticancer half-sandwich metal complexes and can contribute to the rational design of metal compounds with increased biological activity.

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.