A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding

The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3- dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5- hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid–base properties of 1 are studied by potentiometric and spectrophotometric methods, the pKa values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L+, HL and L− forms (HL = mhcpe) and assign the groups involved in the protonation–deprotonation processes. The mhcpe− ligand forms stable complexes with VIVO2+ in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the VIVO–mhcpe species formed. The results are consistent with the formation of VIVO, (VIVO)L, (VIVO)L2, (VIVO)2L2H−2, (VIVO)L2H−1, (VIVO)2L2H−3, (VIVO)LH−2 species and VIVO-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards VIVO2+ is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4- pyridinone (Hdhp). The interaction of VIVO-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and 51V NMR spectroscopy. VIVO–mhcpe–protein ternary complexes are formed in both cases. The binding of VIVO2+ to transferrin (hTF) in the presence of mhcpe involves mainly (VIVO)1(hTF)(mhcpe)1, (VIVO)2(hTF)(mhcpe)1 and (VIVO)2(hTF)(mhcpe)2 species, bound at the FeIII binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the VIVO–mhcpe complexes mainly bind to hTF; the formation of VIVO–hTF–mhcpe complexes occurs in the presence of FeIII as well, distinct EPR signals being clearly obtained for FeIII–hTF and to VIVO–hTF–mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of VIVO–mhcpe complexes under blood plasma conditions in the form of ternary VIV–ligand–protein complexes.The authors are grateful to the Fundo Europeu para o Desenvolvimento Regional, Fundação para a Ciência e Tecnologia (FCT), the POCI 2010 Programme, the Portuguese NMR Network (IST-UTL Center), PEst-OE/QUI/UI0100/2011, University of A Coruña and the Spanish-Portuguese Bilateral Programme (Acção Integrada E-56/05, Acción integrada HP2004- 0074)

Complexation properties of ethylenediaminetetramethylenephosphonic acid (EDTMP) with Al-III and (VO)-O-IV

The complexation properties (including stoichiometries and stability constants of the complexes formed) of ethylenediaminetetramethylenephosphonic acid with AlIII and VIVO were studied in aqueous solution at an ionic strength of 0.2 M KCl, at 25 \ub0C by means of pH-potentiometry. For AlIII both mononuclear (AlLHn) and dinuclear (Al2LHn) species were found in solution, whereas for VIVO only mononuclear complexes were detected. For each metal ion, a solid complex was isolated at acidic pH and was characterized stoichiometrically. 1H and 31P NMR (for AlIII), UV/Vis and EPR (for VIVO) spectra were used to confirm the potentiometric results and to suggest the most probable binding mode of the complexes formed in solution

Solution speciation of potential anticancer metal complexes of salicylaldehyde semicarbazone and its bromo derivative

The stoichiometry and thermodynamic stability of copper(II), vanadium(IV/V), iron(II)/(III) and gallium(III) complexes of salicylaldehyde semicarbazone (SSC, HL) and its 5-bromo derivative (Br-SSC, HL) have been determined by pH-potentiometry, UV–Vis spectrophotometry, EPR, 1H and 51V NMR spectroscopy in 30% (w/w) dimethyl sulfoxide/water solvent mixture. Proton dissociation processes and lipophilicity of the ligands were also studied in detail. Formation of mono-ligand complexes such as [ML], [MLH−1], [MLH−2] was found with copper(II), vanadium(IV/V), while bis-ligand species of iron(II)/(III) and gallium(III) such as [ML2], [ML2H−1] and [ML2H−2] were also detected, in which the ligands coordinate via monoanionic (O−,N1,O) or dianionic (O−,N1,O−) modes. The bromine substituent on the phenol ring has no significant impact on the stability and binding modes but provides a remarkably enhanced lipophilic character, which is advantageous for the bioactivity. The Ga(III)–salicylaldehyde semicarbazone species show unambiguously higher stability; whereas Cu(II) species have somewhat lower stability relative to the corresponding thiosemicarbazone analogues, however no decomposition of the Cu(II) complex was observed even at micromolar concentrations at physiological pH

N,N'-Ethylenebis(pyridoxylideneiminato) and N,N'-Ethylenebis(pyridoxylaminato): Synthesis, Characterization, Potentiometric, Spectroscopic, and DFT Studies of Their Vanadium(IV) and Vanadium(V) Complexes

The Schiff base N,Nprime-ethylenebis(pyridoxylideneiminato) (H2pyr2en, 1) was synthesized by reaction of pyridoxal with ethylenediamine; reduction of H2pyr2en with NaBH4 yielded the reduced Schiff base N,Nprime-ethylenebis(pyridoxylaminato) (H2Rpyr2en, 2); their crystal structures were determined by X-ray diffraction. The totally protonated forms of 1 and 2 correspond to H6L4+, and all protonation constants were determined by pH-potentiometric and 1H NMR titrations. Several vanadium(IV) and vanadium(V) complexes of these and other related ligands were prepared and characterized in solution and in the solid state. The X-ray crystal structure of [VVO2(HRpyr2en)] shows the metal in a distorted octahedral geometry, with the ligand coordinated through the N-amine and O-phenolato moieties, with one of the pyridine-N atoms protonated. Crystals of [(VVO2)2(pyren)2]sdot2 H2O were obtained from solutions containing H2pyr2en and oxovanadium(IV), where Hpyren is the ldquohalfrdquo Schiff base of pyridoxal and ethylenediamine. The complexation of VIVO2+ and VVO2+ with H2pyr2en, H2Rpyr2en and pyridoxamine in aqueous solution were studied by pH-potentiometry, UV/Vis absorption spectrophotometry, as well as by EPR spectroscopy for the VIVO systems and 1H and 51V NMR spectroscopy for the VVO2 systems. Very significant differences in the metal-binding abilities of the ligands were found. Both 1 and 2 act as tetradentate ligands. H2Rpyr2en is stable to hydrolysis and several isomers form in solution, namely cis-trans type complexes with VIVO, and alpha-cis- and beta-cis-type complexes with VVO2. The pyridinium-N atoms of the pyridoxal rings do not take part in the coordination but are involved in acid-base reactions that affect the number, type, and relative amount of the isomers of the VIVO-H2Rpyr2en and VVO2-H2Rpyr2en complexes present in solution. DFT calculations were carried out and support the formation and identification of the isomers detected by EPR or NMR spectroscopy, and the strong equatorial and axial binding of the O-phenolato in VIVO and VVO2 complexes. Moreover, the DFT calculations done for the [VIVO(H2Rpyr2en)] system indicate that for almost all complexes the presence of a sixth equatorial or axial H2O ligand leads to much more stable compounds

Vanadium (IV and V) Complexes of Reduced Schiff Bases Derived from the Reaction of Aromatic o -Hydroxyaldehydes and Diamines Containing Carboxyl Groups

The reduced Schiff bases of salicylaldehyde [and o-vanillin (o-van)] with D,L- and L-diaminopropionic acid (DPA), designated by salDPA, and L-2,4-diaminopentanoic acid [ornithine (Orn)], designated by salOrn, as well as the VIVO2+ and VVO2+ complexes of salDPA were prepared. The compounds were characterised in the solid state and in solution. The structure of H4salDPA+Cl- was determined by X-ray diffraction. Complexation of VIVO2+ and VVO2+ with salDPA and salOrn (only the VIVO system) in aqueous solution was studied by potentiometry, UV/Visible spectroscopy and circular dichroism, as well as by EPR spectroscopy for the VIVO-salDPA system and by 1H- and 51V NMR spectroscopy for the VVO2-salDPA system. Stoichiometries and complex formation constants were determined by potentiometry at 25 °C and I = 0.2 M KCl. Practically only 1:1 complexes were formed in both systems with composition (VO)LH2 and(VO)L in the VIVO-salDPA system, and with composition(VO2)LH and (VO2)L in the VVO2-salDPA system. Spectroscopic data provided information about the most probable binding modes of each stoichiometry. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006