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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.

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.

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.

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.

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.

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.

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.

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).

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.

Heterobimetallic complexes with the evolutionary, well-preserved, histidyl-alanyl-valinyl (HAV) sequence for cadherin targeting, an organometallic Ru core with anticancer activity and a radioactive moiety for imaging may hold potential as theranostic agents for cancer. Visible-light irradiation of the HAVAY-NH2 pentapeptide in the presence of [(η(5)-Cp)Ru(η(6)-naphthalene)](+) resulted in the formation of a full sandwich type complex, (η(6)-Tyr-RuCp)-HAVAY-NH2 in aqueous solution, where the metal ion is connected to the Tyr (Y) unit of the peptide. Conjugation of this complex to 2,2'-(7-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODA-GA) and subsequent metalation of the resulting product with stable ((nat)Ga) and radioactive ((67)Ga) isotope yielded (nat)Ga/(67)Ga-NODA-GA-[(η(6)-Tyr-RuCp)-HAVAY-NH2]. The non-radioactive compounds were characterized by NMR spectroscopy and Mass Spectrometry. The cellular uptake and cytotoxicity of the radioactive and non-radioactive complexes, respectively, were evaluated in various human cancer cell lines characterized by different levels of N- or E-cadherins expression. Results from these studies indicate moderate cellular uptake of the radioactive complexes. However, the inhibition of the cell proliferation was not relevant.

In order to model the metal ion binding capabilities of high molecular mass components of blood the interaction between [(η6-p-cym)Ru(H2O)3]2+ and terminally protected oligopeptides containing three histidyl moieties (Ac-HHH-NH2, Ac-HAHH-NH2, Ac-HAHAH-NH2 and Ac-H*AH*AH*-NH2, where A = L-alanyl, H = L-histidyl, H* = N3-methyl-L-histidyl) were studied by pH-potentiometric, ESI-TOF-MS, circular dichroism and NMR methods at an ionic strength of 0.20 M KCl or KNO3 as well as using density functional theory (DFT) calculations. Protonation constants of the novel peptides are reported. Although for Ac-HHH-NH2 the immediate formation of precipitation with [(η6-p-cym)Ru(H2O)3]2+ hindered any further solution investigations results of the detailed NMR and MS studies revealed that the other three ligands coordinate to the metal ion in rather slow processes via the imidazole moieties forming [(η6-p-cym)RuL]2+ (L = oligopeptide) type species in the slightly acidic, neutral pH-range. At pH ∼7.5 identical binding mode of Ac-HAHH-NH2 and Ac-HAHAH-NH2 in the [(η6-p-cym)RuL]2+ via three imidazole nitrogens was found hindering completely the hydrolysis of the metal ion even at 1:1 metal ion to ligand ratio. At elevated pH MS evidences support the involvement of amide-N donor(s) in metal ion binding too beside partial hydrolysis. 0.20 M KCl medium was found to hinder effectively the hydrolytic processes of the metal ion in the basic pH-range without altering the coordination of the imidazole side chains. Both NMR and DFT results support the imidazole-N1 (“far” or “τ”) over the N3 (“near” or “π”) coordination of the histidyl side chains of all these oligopeptides to the organometallic ruthenium(II) cation.

Mono-, di- and trinuclear Pd(II) complexes of 2,5-pyridinedihydroxamic acid (2,5-pyha) are reported. The X-ray crystal structure of the mononuclear complex, [Pd(en)(2,5-pyha-(1H))]Cl (en = ethylenediamine), was determined exhibiting an (N-py,N) binding mode of 2,5-pyha where (N-py,N) is through a pyridine N and deprotonated hydroxamate N. Such a coordination mode has never previously been observed for a Pd(II) hydroxamato complex. The first examples of di- and trinuclear Pd(II) complexes of a hydroxamic acid are described where one 2,5-pyha ligand acts as a bridge for two and three Pd(en) moieties, respectively. The stability of potential binding modes of 2,5-pyha for a proposed dinuclear complex were investigated by density functional theory at the RI-BP86/def2-TZVP level, in the Turbomole package. It was found that (N-py,N), (O,O')(2) gave the more stable complex where (N-py,N') is through a pyridine N and deprotonated hydroximate N and (O,O')(2) is via the carbonyl oxygen atom and the deprotonated hydroxyl group of the hydroxamic acid at the 2-position on the pyridine ring. A trinuclear complex, [{Pd(en)}(3)(2,5-pyha(4H))](PF6)(2) was isolated and fully characterised. Spectroscopic studies indicate that the coordination modes are (N-py,N), (O,O')(2) and (O,O')(5) where (N-py,N') is through a pyridine N and deprotonated hydroximate N and (O,O') is via doubly deprotonated hydroximate groups at positions 2 and 5 on the pyridine ring. Stability constants for the mono-, di- and trinuclear [Pd(en)](2+) complexes of 2,5-pyridinedihydroxamic acid are also reported. In solution at equimolar concentrations, 2,5-pyha effectively binds one equivalent of Pd(II) to give a mononuclear Pd(II) 2,5-pyha complex and under strongly acidic conditions. In addition formation of stable trinuclear Pd(II) 2,5-pyha complexes are favoured at an excess of Pd(II).

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 pH4.0 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 pH5.0, 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 pH4.0. 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.

Two histidinehydroxamic acid derivatives ( N -methyl-histidinehydroxamic acid, N- Me-Hisha and Z -histidinehydroxamic acid, Z -Hisha) have been synthesized and their complexation with Cu 2+ -, Ni 2+ - and Zn 2+ -ions has been studied by using pH-potentiometric, UV–Vis, CD, 1 H NMR, EPR and ESI-MS methods. Both of the two new derivatives contain one donor atom less compared to the histidinehydroxamic acid (Hisha). In the case of N -Me-Hisha the hydroxamate-N as donor is eliminated, while the coordination of the amino- N of Z- Hisha is not possible at all. With the ambidentate N -Me-Hisha, the histamine-type coordination mode is favoured if the metal ion is Ni 2+ and the bis-[NH 2 ,N imid ] complex is the most stable in this system. The mixed type, [NH 2 ,N imid ] + [O,O], coordination mode dominates in the Cu 2+ - N -Me-Hisha complexes, while different low stability mono-chelated linkage isomers are formed with Zn 2+ . With Z- Hisha (having poor water solubility) hydroxamate-type coordination mode predominates in low stability complexes in the Ni 2+ and Zn 2+ containing systems. Interestingly, the interaction with Cu 2+ is very strong and results in the formation of a high stability 12-MC-4 type metallacrown with involvement of 5-membered and 7-membered chelates.

Complex formation of primary dipeptide hydroxamic acids, L-Ala-L-AlaNHOH and L-Ala-L-SerNHOH, as well as the corresponding Z-protected ones, Z-L-Ala-L-AlaNHOH and Z-L-Ala-L-SerNHOH (Z = benzyloxycarbonyl), with iron(III), aluminium(III), nickel(II), copper(II) and zinc(II) was studied in aqueous solution by pH-potentiometric and spectroscopic (UV–Vis, EPR, CD, 1H NMR) methods. The exclusive formation of [O,O] chelated hydroxamate complexes was found with iron(III) and aluminium(III) with all the ligands. Formation of linkage isomers with the involvement of either [O,O] hydroxamate or [NH2,CO] chelates was detected both in the zinc(II)-L-Ala-L-AlaNHOH and -L-Ala-L-SerNHOH systems. Upon increasing the pH, none of these chelating sets are capable of preventing the hydrolysis of the metal ion. The formation of stable complexes was found in the nickel(II) and copper(II) systems above pH ∼ 6 with a [NH2, Namide, Nhydrox.] binding mode after deprotonation and coordination of the peptide amide and the hydroxamate group. With an excess of copper(II), the formation of trinuclear [Cu3HxL2]x+4 type (x = −4 to −6) complexes as the major species was also detected. Blocking the terminal amino group in the Z-protected ligands results in a dramatic decrease of the nickel(II) and zinc(II) binding strengths, and insoluble complexes with copper(II). No indication was found for the role of the hydroxyl group of the serine moiety in metal ion binding.

Complex forming capabilities of [(η(6)-p-cymene)Ru(H2O)3](2+) with aminohydroxamates (2-amino-N-hydroxyacetamide (α-alahaH), 3-amino-N-hydroxypropanamide (β-alahaH) and 4-amino-N-hydroxybutanamide (γ-abhaH)) having the primary amino group in different chelatable position to the hydroxamic function were studied by pH-potentiometry, NMR and MS methods. Formation of stable [O,O] and mixed [O,O][N,N] chelated mono- and dinuclear species is detected in partially slow with α-alahaH and β-alahaH or in fast processes with γ-abhaH and the formation constants of the complexes present in aqueous solution are reported. Synthesis, spectral (NMR, IR) and ESI mass spectrometric characterization of novel dinuclear α-alaninehydroximato complexes containing the half-sandwich type Ru(II) core is described. The crystal and molecular structure of [{(η(6)-p-cymene)Ru}2(μ(2)-α-alahaH-1)(H2O)Br]Br∙H2O (1) and [{(η(6)-p-cymene)Ru}2(μ(2)-α-alahaH-1)(H2O)Cl]BF4∙H2O (2) was determined by single crystal X-ray diffraction method. In the complexes one half-sandwich core is coordinated by a hydroxamate [O,O] chelate while the other one by [Namino,Nhydroxamate] fashion of the bridging ligand. In both cases the remaining coordination sites of one of the Ru cores are taken by a halide ion whiles the other one by a water molecule. Reaction of 2 with 9-methylguanine indicates the N7 coordination of this simple DNA model. Complexes 1 and 2 were tested for their in vitro cytotoxicity using human-derived cancer cell lines (A2780, MCF-7, SKOV-3, HCT-116, HeLa) and showed no anti-proliferative activity in the micromolar concentration range.

In order to model the biotransformation reactions of half-sandwich type platinum metal complexes with potential antiproliferative activity in the serum the interaction between [(η 6 - p -cym)Ru(H 2 O) 3 ] 2+ and N-methylimidazole was studied in aqueous 0.20 M KNO 3 or KCl medium with the combined use of pH-potentiometric, NMR, UV–Vis and ESI-TOF-MS techniques. The results indicate that up to three ligands can coordinate to the metal ion in rather slow processes resulting in mononuclear species. In the absence of chloride ions various mixed hydroxido complexes are also identified under basic conditions. Chloride was found to take the free coordination site(s) of the metal ion in the 1:1 and 1:2 species and to hinder effectively the hydrolytic processes. Stability constants of the species are reported. The results indicate that even this monodentate model ligand, N-methylimidazole, forms stable complexes with the metal ion under physiologically relevant conditions at 1:3 metal to ligand ratio and prevents it from complete hydrolysis at pH = 7.4.

The hydrolysis of vanadium(III) and the complex formation reactions between V(III) and weakly coordinating [glycine (GLY), DL-aspartic acid (ASP), D-penicillamine (PEN), DL-histidine (HIS)] or strongly coordinating [N,O] donor [picolinic (PIC) or 6-methylpicolinic acid (MePIC)] and [O,O] donor [maltol (MALT), 1,2-dimethyl-3-hydroxy-4-(1H)-pyridinone (DHP), tiron (TIR)] ligands were studied at 25.0 °C and an ionic strength of 0.20 M (KCl) in aqueous solution using combined pH-potentiometric and UV-vis spectroscopic techniques. Although some interaction between the amino acids and V(III) was found, we could not obtain reliable models for these systems owing to the intensive hydrolysis of the metal ion and the formation of polynuclear hydroxo complexes. With pyridine carboxylates or [O,O] donor ligands 1:1, 1:2 (in the latter case, also 1:3 species) were found to be present as major complexes in solution. The similarities and differences in binding V(III) by these ligands are discussed.

Three new dihydroxamic acids (HO(CH 3 )NCO–(CH 2 ) 2 –CO–NH–(CH 2 ) x –CON(CH 3 )OH where the x values are 4; 3 and 2, and the compounds are abbreviated as 2,4-DIHA, 2,3-DIHA and 2,2-DIHA), containing the peptide group in a certain position to one of the two functional groups and in different distances to the other one, were synthesized and their complexation with Fe(III), Mo(VI) and V(V) was studied by pH-potentiometric, spectrophotometric and in some cases by CV methods to evaluate the redox behaviour of the Fe(III) complexes and assess their potential biological activity as siderophore models. All these compounds are structural models for the natural siderophore, desferrioxamine B (DFB). The results were compared to those of the complexes of 2,5-DIHA having the same connecting chain structure and length as DFB has, and the effects of the length of the connecting chain on the co-ordination mode and on the stability of the complexes formed were evaluated. Very similar stability of the mono-chelated complexes formed with all these dihydroxamic acids was found. All the results obtained suggest that one dihydroxamic acid (even the 2,2-DIHA) is able to complete the four coordination sites of a MoO 2 2+ core forming simple mononuclear complexes. Favoured monomeric structures of the bis-chelated complexes of these dihydroxamic acids are also suggested with V(V) having the smallest ionic radius among the three metal ions studied. In the case of iron(III), however, clear indication was obtained for the slightly different complexation behaviour of 2,2-DIHA. Namely, the formation of the mononuclear bis-chelated complex with this shortest ligand seems to have sufficient strain to induce the formation of bimetallic species such as [Fe(2,2-DIHA) 2 Fe)] 2+ .

The complex formation between Cu(II) and 1-hydroxyethane-1,1-diphosphonic acid was studied by means of pH-potentiometry and spectroscopy (UV–Vis and EPR). Speciation revealed the formation of a trinuclear complex [Cu3A3]6− besides the mononuclear 1:1 and 1:2 species. In the complex [Cu3A3]6− , which is not formed with other diphosphonic derivatives, the ligands adopt chelating and bridging modes via the four O atoms of the two phosphonates, the alcoholic-OH groups remaining in the protonated form.

The interactions of quinolone ciprofloxacin (cfH) and oxovanadium(IV) were studied by various methods. Green crystals of a complex [V(IV)O(cf)(2)(H(2)O)] were isolated and the molecular connectivities established, although the crystal structure was not perfectly refined due to the instability of the crystals. Based on a plausible interpretation of the data sets, two cf anions bidentately coordinate to a vanadyl cation through carboxylate and carbonyl oxygen atoms; in addition, there is a water molecule in the coordination sphere. Solution techniques (cyclic voltammetry, electronic and electron paramagnetic resonance spectroscopy, potentiometric measurements) confirmed the presence of various species in the solution, the composition of which strongly depends on the conditions in the system. The antibacterial activity of the complex against various microorganisms was tested and it was established that its activity is similar to that of free ciprofloxacin.

A new tetradentate ligand having two 3-hydroxy-4-pyridinonate moieties and one carboxylate group appended to a cyclohexane backbone is reported, together with the corresponding bidentate hydroxypyridinonate pendant arm. The synthesis and characterization of these ligands, as well as their complexation properties towards the first transition series of metal ions M(II) (M=Cu, Ni, Zn) in aqueous solution, are described and discussed herein. The tetradentate ligand forms quite stable complexes with this series of metal ions and in solution, it is proved to be a much more effective chelator than the corresponding bidentate derivative. The stability constants of the complexes formed with this set of bivalent ions follow the Irving–Williams order Ni Zn. The carboxylic group has no interaction with the metal centre, thus remaining free for potential interaction with biological ligands (e.g. proteins).

Three new dihydroxamic acids (HO(CH3)NCO(CH2)xCONH(CH2)yCON(CH3)OH, where the related x and y values are as follows: 2,5; 3,4 and 3,3) with different length of the connecting chains containing the peptide group in different positions between the two functional groups were synthesized and their complexation with Fe(III), Mo(VI) and V(V) were studied by pH-potentiometric and spectrophotometric methods. Both the structure and length of the connecting chain in the 2,5-dihydroxamic acid (2,5-DIHA) are the same as those in the natural siderophore, desferrioxamine B (DFB). Although the stability of the monochelated complexes formed with all three dihydroxamic acids are similar, 2,5-DIHA forms significantly more stable bis-chelated complexes than the other two ligands with the three metal ions studied. The results support the hypothesis that the arrangement of the two chelating functions in 2,5-DIHA is in a proper preorganization for the coordination in octahedral complexes to metal ions having similar ionic radius as iron(III) has.

The speciation and solution structures of the binary VO(IV) complexes of mertcaptopropionylglycine and its ternary complexes with 2,2′-bipyridyl, tiron, maltol and oxalic acid were studied by pH-potentiometric and spectroscopic (EPR and UV–Vis) methods. The thiolate-S− donor of mercaptopropionylglycine proved to be an efficient anchoring donor which binds VO(IV) strongly enough to be able to promote deprotonation and subsequent coordination of the peptide–amide group. Ternary complex formation and the promotion of amide deprotonation were found to be favoured with the (N,N) donor 2,2′-bipyridyl, but disfavoured with the (O,O) donor ligands tiron, maltol and oxalic acid.

The equilibria in the system V(IV)O(2+)-glutathione in aqueous solution were studied in the pH range 2-11 by a combination of pH-potentiometry and spectroscopy (EPR, visible absorption and circular dichroism). The results of the various methods are consistent and the equilibrium model includes the species MLH(3), MLH(2), MLH, ML(2)H(2), MLH(-1), and MLH(-2) and several hydrolysis products (where H(4)L denotes totally protonated glutathione); individual formation constants and spectra are given. ML(2)H(2) is the predominant species at physiological pH. Plausible structures for each stoichiometry are discussed. The related V(IV)O(2+) systems of S-methylglutathione and gamma- L-glutamyl- L-cysteinyl ethyl ester were studied by means of the same spectroscopic techniques in order to support the established binding modes for the glutathione complexes. The importance of glutathione and oxidized glutathione in binding V(IV)O(2+) in cells is assessed.

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

The equilibria in the system VO2+ +oxidized glutathione in aqueous solution have been studied in the pH range 2-11 by a combination of pH potentiometry and spectroscopy (EPR, visible absorption and circular dichroism). The results of the various methods are self-consistent and the equilibrium model includes the species MLH4, MLH3, MLH2, MLH, ML, MLH(-1), MLH(-2) and several hydrolysis products (where H4L denotes oxidized glutathione); individual formation constants and spectra are given. Plausible structures for each stoichiometry are discussed.

Potentiometric, spectral and 1H NMR relaxation studies are reported on the complex formation of VO(IV) with the bidentate chelating ligands oxalic and malonic acids, of a dicarboxylic nature, and maltol and kojic acid, of the hydroxy-4-pyrone type. Complexes with stochiometries VOA and VOA2 were characterised in aqueous solution. Two main features were established for the complex systems. It was found that five-membered ring chelation favours the cis arrangement in the bis complexes of maltol and kojic acid to a higher extent than in those of oxalic and malonic acids. Moreover, previous investigations of VO(IV) binding to maltol or its analogues did not consider the formation of hydroxo species. Formation of dihydroxo bridged dimeric complexes of stoichiometry (VOAH−1)2 and monomeric hydroxo species VOA2H−1 or VOA2(OH), are now taken into account in order to explain the equilibrium and spectroscopic results. 1H NMR relaxation measurements strongly suggest an equilibrium between the two isomers of the bis complexes.

The iron release mechanism from protonated ferric enterobactin [Fe(III)(enterobactinH(3))] via the salicylate binding mode was probed. For this purpose, a tripodal dodecadentate ligand incorporating three salicylamide (OO) and three bipyridine (NN) binding sites was synthesized as well as iron complexes thereof. It was shown that a ferric ion coordinates selectively to the hard salicylamides and a ferrous ion binds to the softer bipyridines. Upon reduction or oxidation, the iron translocates reversibly and intramolecularly from one site to the other, thus displaying switchlike properties. Both states were characterized by cyclic voltammetry and visible and Mössbauer spectroscopy. The Mössbauer spectrum for the ferric complex is fully consistent with that obtained by Pecoraro et al. upon lowering the pH of [Fe(III)(enterobactin)](3)(-) solutions (Pecoraro, V. L., et al. J. Am. Chem. Soc. 1983, 105, 4617), thus supporting the alternative iron release mechanism from enterobactin via the salicylate binding mode.

Complex formation between oxovanadium(IV) and several diazole derivatives (imidazole-4-acetic, imidazole-4,5-dicarboxylic and pyrazole-3,5-dicarboxylic acid) was studied in aqueous solution by pH-potentiometric and spectroscopic (electron paramagnetic resonance and electronic absorption) techniques. The results show that the imidazole-4-acetate ligand, being suitable for bidentate coordination, forms monomeric or mixed hydroxo-bridged species. In the case of the dicarboxylic acids both having two bidentate sites for metal binding the formation of tetrameric or dimeric complexes is strongly favored. Pyrazole-3,5-dicarboxylic acid forms dinuclear, while imidazole-4,5-dicarboxylic acid forms cyclic tetrameric species, both types containing diazolate bridges. There is evidence for the VO2+-supported deprotonation of the imidazole N1 (pyrrole-type) group at pH as low as 5 in aqueous solution.

pH-Metric and spectroscopic (absorption and EPR) studies were made on the proton and copper(II) complexes of phosphonic and mixed carboxylic-phosphonic derivatives of iminodiacetic acid and nitrilotriacetic acid. The stoichiometries and stability constants of the complexes formed were determined at 25°C and at an ionic strength of 0.20 mol dm −3 (KCl). Stability data and spectroscopic measurements revealed that in spite of the increased basicity of the coordinating phosphonate donors, the carboxylic analogues remain more efficient copper(II) binders as the larger space requirement and higher electrostatic repulsion between the binegative phosphonate donors overcompensate the former effect. The PO 3 2− /CO 2 − substitution results in a significant rhombic distortion in the geometry of the complexes.

To explore the role of the side chain alcoholic OH group in metal ion binding the interaction between [Ru(η6-p-cym)(H2O)3]2+ (p-cym = 1-isopropyl-4-methylbenzene) and dl -serine (serH) or dl -isoserine (iseH) was studied by means of pH-potentiometry, 1H NMR and ESI-MS techniques in aqueous solution. The results indicate that, unlike simple amino acids with no donor atom in the side chain, ser and especially ise are potent ruthenium ion binders and are capable of preventing the metal ion from significant hydrolysis at pH = 7.4 due to the metal ion assisted deprotonation and coordination of the alcoholic OH function and forming stable joined chelates with [NH2, COO−, O−] donor set. Comparison of the speciations obtained for the two systems indicates that ise with (6 + 5) membered joined chelates of the [NH2, COO−, O−] donor set forms more stable complexes than ser which is suitable for (5 + 6) [NH2, COO−, O−] coordination. Analysis of the effect of the replacement of the amino group in the [NH2, COO−, O−] donor set of ise by a COO− (citrate) reveals that the latter is more effective in the acidic pH range; the two donor sets show comparable metal ion strengths under physiologically relevant conditions and ise is found to be a better metal ion binder in the basic pH range than citrate due to the basicity difference of the –NH2 and –COO− groups in ise and citrate ligands, respectively. [Ru(η6-p-cym)ise](CF3SO3)·0.5H2O (1) with [NH2, COO−, OH] coordination of the ligand was also synthesized and characterized in the solid state by various analytical techniques.

The complex-formation processes taking place in the systems containing VO(IV) and d-, l-, dl- or meso -tartaric acid or citric acid in aqueous solution were re-examined by combined use of pH potentiometry and spectroscopic (EPR and electronic absorption) methods. The results allowed a full characterization of the dinuclear species existing in the VO(IV)— d-, l- and dl -tartrate systems and indicated a different complexation behaviour in the corresponding meso -tartrate system. As its conformation is unfavourable for dimer formation, the meso ligand yields predominantly cyclic trinuclear species, one of them exhibiting distinctive EPR features. In the VO(IV)-citrate system, dinuclear species with structures different from those of the VO(IV) tartrates are suggested.

The interaction of oxovanadium(IV) ion with diphosphoric and triphosphoric acids in aqueous solution was investigated over the measurable pH range by means of potentiometry, electronic absorption and EPR measurements. The results show that both diphosphate and triphosphate, partially or fully deprotonated depending on pH, are able to chelate the metal ion to yield several mononuclear species. With triphosphate, there is no evidence for the formation of a species analogous to the already reported and well-characterized trinuclear complex formed by diphosphate acting as a chelating and bridging ligand through the four unshared oxygen atoms.

Complex formation between oxovanadium(IV) and vanadate(V) with deferoxamine B was investigated in aqueous solution by EPR, electronic absorption spectroscopy, 51V NMR, ans pH-potentiometry. The reaction scheme implies that in very acidic media, reversible oxygen displacement occurs on the metal ion to yield nonoxo V(IV) or V(V) complexes, which exhibit distinct EPR and 51V NMR spectral features, respectively. In these species, the bare vanadium ions are coordinated to the three hydroxamic functions of the ligand. With increasing pH, oxo coordination is restored and “normal” VO(IV) and VO2(V) complexes are formed with metal bonding to one or two hydroxamic functions of the ligand.

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

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. Stability constants of the metal complexes formed with SAHA and N-Me-SAHA in a DMSO/H(2)O 70/30%(v/v) mixture are described. A novel crystal structure of SAHA together with a novel synthesis for N-Me-SAHA are also reported.

Potentiometric (pH titrations) and spectroscopic (electron paramagnetic resonance) methods have been used to determine the thermodynamic stability constants of the various VO(2+) complexes formed after the interaction of four insulin-enhancing vanadium compounds, [VO(6-mepic)(2)], cis-[VO(pic)(2)(H(2)O)], [VO(acac)(2)], and [VO(dhp)(2)], where 6-mepic, pic, acac, and dhp indicate the deprotonated forms of 6-methylpicolinic acid, picolinic acid, acetylacetone, and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone, with high molecular mass [human serum apotransferrin (hTf) and human serum albumin (HSA)] and low molecular mass (lactate) components of blood serum. In particular, log beta values for the formation of (VO)hTf (13.0 +/- 0.5), (VO)(2)hTf (25.5 +/- 0.5), (VO)HSA (9.1 +/- 1.0), (VO) (2) (d) HSA (20.9 +/- 1.0), cis-VO(dhp)(2)(hTf) (25.5 +/- 0.6), cis-VO(dhp)(2)(HSA) (25.9 +/- 0.6), (VO)hTf(lact) (14.5 +/- 0.8), (VO)(2)hTf(lact)(2) (28.5 +/- 0.8), (VO)hTf(pic) (15.6 +/- 0.8), and (VO)(2)hTf(pic)(2) (30.4 +/- 0.8) were determined. The values of the stability constants were used to compare the calculated composition of ternary and quinary systems with that recently proposed by some of us through electron paramagnetic resonance and density functional theory methods (Sanna et al. in Inorg. Chem. 49:174-187, 2010) and to predict the distribution of VO(2+) ion in blood serum when one of the four insulin-enhancing vanadium compounds studied, [VO(carrier)(2)], is administered.