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Vanadium compounds have frequently been proposed as therapeutics, but their application has been hampered by the lack of information on the different V-containing species that may form and how these interact with blood and cell proteins, and with enzymes. Herein, we report several resolved crystal structures of lysozyme with bound V IV O 2+ and V IV OL 2+ , where L=2,2'-bipyridine or 1,10-phenanthroline (phen), and of trypsin with V IV O(picolinato) 2 and V V O 2 (phen) + moieties. Computational studies complete the refinement and shed light on the relevant role of hydrophobic interactions, hydrogen bonds, and microsolvation in stabilizating the structure. Noteworthy is that the trypsin-V V O 2 (phen) and trypsin-V IV O(OH)(phen) adducts correspond to similar energies, thus suggesting a possible interconversion under physiological/biological conditions. The obtained data support the relevance of hydrolysis of V IV and V V complexes in the several types of binding established with proteins and the formation of different adducts that might contribute to their pharmacological action, and significantly widen our knowledge of vanadium-protein interactions., (© 2022 Wiley-VCH GmbH.)

Two novel bicapped Keggin polyoxidovanadates with organic cations, (C 6 H 8 N) 5 [H 4 PV 14 O 42 ]·5H 2 O (1) and (C 6 H 14 N 4 ) 2 (NH 4 )[H 4 PV 14 O 42 ]·11H 2 O (2), (PV 14 O 42 6- = PV14, C 6 H 7 N = 3-picoline and C 6 H 12 N 4 = methenamine) were synthesized. These compounds were isolated and characterized in the solid state and in solution by elemental analysis, powder X-ray diffraction, FTIR, UV-vis, 51 V, 31 P, 13 C and 1 values, the DFT results also indicate that molecular reduction is energetically more favourable in protonated PV14 anions. Upon the addition of PV14 anions to bovine serum albumin (BSA) up to a ratio of 1 : 1, the fluorescence decreased by 45% for both 1 and 2, indicating that the interaction of vanadium-containing species with this protein takes place; log( K a values, the DFT results also indicate that molecular reduction is energetically more favourable in protonated PV14 anions. Upon the addition of PV14 anions to bovine serum albumin (BSA) up to a ratio of 1 : 1, the fluorescence decreased by 45% for both 1 and 2, indicating that the interaction of vanadium-containing species with this protein takes place; log( K SV ) values of ca. 5.5 were obtained in both systems. Upon the addition of 1 or 2 to solutions of calf-thymus DNA (ctDNA), changes were observed in the UV-vis absorption and circular dichroism spectra. The significance of the changes observed is discussed considering the several V-containing species that form in the solution.

Novel dibasic Schiff bases with three tridentate sites were obtained from the condensation of the triketone 2,4,6-triacetylphloroglucinol (H3ptk) with four different hydrazides, benzoyl hydrazide (bhz), furoyl hydrazide (fah), isonicotinoyl hydrazide (inh) and nicotinoyl hydrazide (nah): H6ptk(bhz)3I, H6ptk(fah)3II, H6ptk(inh)3III and H6ptk(nah)3IV. These ligand precursors I-IV, each being an ONO donor, are tricompartmental building blocks able to form trinuclear complexes having C3 symmetry. The reaction of I-IV with [VIVO(acac)2] leads to the formation of [{VIVO(H2O)}3(ptk(bhz)3)] 1, [{VIVO(H2O)}3(ptk(fah)3)] 2, [{VIVO(H2O)}3(ptk(inh)3)] 3, and [{VIVO(H2O)}3(ptk(nah)3)] 4. In methanol/aqueous solutions of M2CO3 (M+ = Na+, K+ and Cs+), these complexes are slowly converted into dioxidovanadium(v) compounds, namely, M3[(VVO2)3{ptk(bhz)3}]·6H2O [M+ = K+5, Na+9, Cs+13], M3[(VVO2)3{ptk(fah)3}]·6H2O [M+ = K+6, Na+10, Cs+14], M3[(VVO2)3{ptk(inh)3}]·6H2O [M+ = K+7, Na+11, Cs+15] and M3[(VVO2)3{ptk(nah)3}]·6H2O [M+ = K+8, Na+12, Cs+16]. All ligand precursors and complexes are characterized by various techniques such as FT-IR, UV/Visible, EPR, NMR (1H, 13C and 51V), elemental analysis, thermal studies, cyclic voltammetry (CV) and single-crystal X-ray analysis. X-ray diffraction studies of complexes K2.7[{(VVO2)3ptk(fah)3}]·11.5H2O·MeOH 6a, Cs3[{(VVO2)3ptk(bhz)3}]·7H2O 13a and Cs3[{(VVO2)3ptk(nah)3}]·7.3H2O 16a reveal their distorted square pyramidal geometry by coordinating through phenolate oxygen (of ptk), azomethine nitrogen and enolate oxygen (of hydrazide) atoms. The reactivity of complexes 5-16 and their catalytic potential were screened towards their peroxidase mimetic activity in the oxidation of dopamine to aminochrome driven by H2O2 as an oxidant. The conversion of dopamine to aminochrome with different catalysts was monitored by HPLC showing high activity under mild conditions with good conversions within 1 h. Kinetic studies using compounds 13-16 as catalyst precursors reveal that the reaction follows a Michaelis-Menten-like kinetics.

Previous studies generally agree that in the blood serum vanadium is transported mainly by human serum transferrin (hTF). In this work through the combined use of electrochemical techniques, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry and small-angle X-ray scattering (SAXS) data it is confirmed that both V IV and V V bind to apo-hTF and holo-hTF. The electrochemical behavior of solutions containing vanadate(V) solutions at pH=7.0, analyzed by using two different voltammetric techniques, with different time windows, at a mercury electrode, Differential Pulse Polarography (DPP) and Cyclic Voltammetry (CV), is consistent with a stepwise reduction of V V →V IV and V IV →V II . Globally the voltammetric data are consistent with the formation of 2:1 complexes in the case of the system V V -apo-hTF and both 1:1 and 2:1 complexes in the case of V V -holo-hTF; the corresponding conditional formation constants were estimated. MALDI-TOF mass spectrometric data carried out with samples of V IV OSO 4 and apo-hTF and of NH 4 V V O 3 with both apo-hTF and holo-hTF with V:hTF ratios of 3:1 are consistent with the binding of vanadium to the proteins. Additionally the SAXS data suggest that both V IV OSO 4 and NaV V O 3 can effectively interact with human apo-transferrin, but for holo-hTF no clear evidence was obtained supporting the existence or the absence of protein-ligand interactions. This latter data suggest that the conformation of holo-hTF does not change in the presence of either V IV OSO 4 or NH 4 V V O 3 . Therefore, it is anticipated that V IV or V V bound to holo-hTF may be efficiently up-taken by the cells through receptor-mediated endocytosis of hTF., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Several mixed ligand vanadium and copper complexes were synthesized containing 8-hydroxyquinoline (8HQ) and a ligand such as picolinato (pic(-)), dipicolinato (dipic(2-)) or a Schiff base. The complexes were characterized by spectroscopic techniques and by single-crystal X-ray diffraction in the case of [V(V)O(L-pheolnaph-im)(5-Cl-8HQ)] and [V(V)O(OMe)(8HQ)2], which evidenced the distorted octahedral geometry of the complexes. The electronic absorption data showed the presence of strong ligand to metal charge transfer bands, significant solvent effects, and methoxido species in methanol, which was further confirmed by (51)V-NMR spectroscopy. The structures of [Cu(II)(dipic)(8HQ)]Na and [V(IV)O(pic)(8HQ)] were confirmed by EPR spectroscopy, showing only one species in solution. The biological activity of the compounds was assessed through the minimal inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis (Mtb) and the cytotoxic activity against the cisplatin sensitive/resistant ovarian cells A2780/A2780cisR and the non-tumorigenic HEK cells (IC50 values). Almost all tested vanadium complexes were very active against Mtb and the MICs were comparable to, or better than, the MICs of drugs, such as streptomycin. The activity of the complexes against the A2780 cell line was dependent on incubation time presenting IC50 values in the 3-14 μM (at 48 h) range. In these conditions, the complexes were significantly (*P<0.05-**P<0.001) more active than cisplatin (22 μM), in the A2780 cells and even surpassing its activity in the cisplatin-resistant cells A2780cisR (2.4-8 μM vs. 75.4; **P<0.001). In the non-tumorigenic HEK cells poor selectivity toward cancer cells for most of the complexes was observed, as well as for cisplatin., (Copyright © 2014 Elsevier Inc. All rights reserved.)

As a contribution to the identification of the relevant species for biological activity and the understanding of structure-activity relationships of [V(IV)O(L-2H)(NN)] antitrypanosomal complexes (NN is a bidentate polypyridyl DNA intercalator; L is a tridentate salicylaldehyde semicarbazone derivative), new [V(V)O2(L-2H)] complexes and [V(IV)O(L-2H)(NN)] complexes including bipy or dppz (dipyrido[3,2-a: 2',3'-c]phenazine) co-ligands are prepared and characterized in the solid state and in solution. Their activity is evaluated on Trypanosoma cruzi. The lipophilicity, as structural descriptor related to bioactivity, of the whole [V(IV)O(L-2H)(NN)] series is determined. Furthermore, the antiproliferative effect of those new compounds showing activity against T. cruzi is evaluated on the genetically related parasite T. brucei with the aim to develop broad spectrum agents. The new [V(IV)O(L-2H)(dppz)] complexes are about ten to fifteen times more toxic to T. cruzi than the bipy analogues and show quite good in vitro activity on T. brucei brucei. They are shown to interact with DNA, suggesting that this biomolecule may be the parasite target. The stability of the V(IV)O-complexes in solution is accessed by several techniques. Globally the data suggest that the relevant species for biological activity are the [V(IV)O(L-2H)(NN)] compounds, their order of activity being dependent on the NN nature, but not much on the substitution on the salicylaldehyde semicarbazone moiety. A parabolic relationship between biological response and lipophilicity (determined as RM=log [(1/Rf)-1] by a TLC method) is obtained. From this correlation an optimum RM value, close to 1.44, was found, which may be used as design guide for future development of antitrypanosomal compounds., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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 pK(a) 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 V(IV)O(2+) in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the V(IV)O-mhcpe species formed. The results are consistent with the formation of V(IV)O, (V(IV)O)L, (V(IV)O)L2, (V(IV)O)2L2H(-2), (V(IV)O)L2H(-1), (V(IV)O)2L2H(-3), (V(IV)O)LH(-2) species and V(IV)O-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards V(IV)O(2+) 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 V(IV)O-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and (51)V NMR spectroscopy. V(IV)O-mhcpe-protein ternary complexes are formed in both cases. The binding of V(IV)O(2+) to transferrin (hTF) in the presence of mhcpe involves mainly (V(IV)O)1(hTF)(mhcpe)1, (V(IV)O)2(hTF)(mhcpe)1 and (V(IV)O)2(hTF)(mhcpe)2 species, bound at the Fe(III) 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 V(IV)O-mhcpe complexes mainly bind to hTF; the formation of V(IV)O-hTF-mhcpe complexes occurs in the presence of Fe(III) as well, distinct EPR signals being clearly obtained for Fe(III)-hTF and to V(IV)O-hTF-mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of V(IV)O-mhcpe complexes under blood plasma conditions in the form of ternary V(IV)-ligand-protein complexes.

Searching for prospective metal-based drugs for the treatment of Chagas disease, a new series of ten mixed-ligand oxidovanadium(IV) complexes, [V(IV)O(L-2H)(NN)], where L is a tridentate salicylaldehyde semicarbazone derivative (L1-L5) and NN is either 5-amine-1,10-phenanthroline (aminophen) or 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), were synthesized. The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate through both nitrogen donor atoms in an axial-equatorial mode. The stability of the complexes in solution was investigated by EPR and (51)V-nuclear magnetic resonance spectroscopies. The complexes were evaluated in vitro for their activities against Trypanosoma cruzi (T. cruzi), the parasite responsible for the disease, and their selectivity was analyzed using J-774 murine macrophages, as a mammalian model. All the complexes are more active than both the reference drug Nifurtimox and the previously reported [V(IV)O(L-2H)(NN)] complexes. In general they are more active than the corresponding free NN ligands. Complexation led to highly increased selectivities towards the parasite. In addition, the lipophilicity of the compounds was determined and correlated with the observed activity in order to perform a QSAR (quantitative structure-activity relationship) study. A clear quadratic correlation is found. This study also confirms the influence of the structure of the co-ligand on the anti-T. cruzi effect. To get insight into the mechanism of action of the compounds, the changes in biochemical pathways promoted by two of the most active and most selective complexes are studied by analyzing a few of the parasite excreted metabolites by (1)H NMR spectroscopy. The combined information suggests that the mitochondrion could be a target for these complexes. Furthermore, DNA was preliminarily evaluated as a potential target by using atomic force microscopy (AFM), which showed that the complexes display an ability to interact with this biomolecule.

Searching for new promising metal-based hits against Trypanosoma cruzi and Leishmania parasites, two related oxidovanadium(IV) N-acylhydrazone complexes, [V(IV)O(LASSBio1064-2H)(H2O)], 1, and [V(IV)O(LASSBio1064-2H)(phen)]·(H2O), 2, where LASSBio1064=(E)-N'-(2-hydroxybenzylidene-4-chlorobenzohydrazide and phen = 1,10-phenanthroline, were synthesized and characterized in the solid state and in solution by elemental analysis, conductimetric measurements and ESI-MS, FTIR, EPR and (51)V NMR spectroscopies and were evaluated on T. cruzi and Leishmania major. In addition, their unspecific cytotoxicity was tested against murine macrophages. Furthermore, to provide insight into the possible mechanism of its antiparasitic action, [VO(LASSbio1064-2H)(phen)].(H2O) was tested for its DNA interaction ability on plasmid DNA by atomic force microscopy (AFM) and on CT DNA by using DNA viscosity measurements and fluorescence spectroscopy. Both complexes were active in vitro against the epimastigote form of T. cruzi (Tulahuen 2 strain) showing IC50 values of the same order or significantly lower than that of the reference trypanosomicidal drug Nifurtimox. However, only the mixed-ligand oxidovanadium(IV) complex 2, which includes phen in its coordination sphere, showed activity on L. major promastigotes with a IC50 value of 22.1 ± 0.6 μM. The compounds show low toxicity on mammalian cells (IC50 > 100 μM). DNA interaction studies showed that the mixed-ligand complex is able to interact with this biomolecule probably through an intercalative mode, pointing out at DNA as a potential target in the parasite. The results suggest that [V(IV)O(LASSBio1064-2H)(phen)]·(H2O) may be a promising compound for further drug development stages., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

In the search for new therapeutic tools against diseases produced by kinetoplastid parasites five vanadyl complexes, [V(IV)O(L-2H)(phen)], including 1,10-phenanthroline (phen) and tridentate salicylaldehyde semicarbazone derivatives as ligands have been synthesized and characterized in the solid state and in solution by using different techniques. EPR suggested a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and phen coordinated in an equatorial/axial mode. The compounds were evaluated in vitro on epimastigotes of Trypanosoma cruzi, causative agent of Chagas disease, Leishmania panamensis and Leishmania chagasi and on tumor cells. The complexes showed higher in vitro anti-trypanosomal activities than the reference drug Nifurtimox (IC(50) values in the range 1.6-3.8 μM) and increased activities in respect to the free semicarbazone ligands. In vitro activity on promastigote and amastigote forms of Leishmania showed interesting results. The compounds [VO(L1-2H)(phen)] and [VO(L3-2H)(phen)], where L1 = 2-hydroxybenzaldehyde semicarbazone and L3 = 2-hydroxy-3-methoxybenzaldehyde semicarbazone, resulted active (IC(50) 2.74 and 2.75 μM, respectively, on promastigotes of L. panamensis; IC(50) 19.52 and 20.75 μM, respectively, on intracellular amastigotes of L. panamensis) and showed low toxicity on THP-1 mammalian cells (IC(50) 188.55 and 88.13 μM, respectively). In addition, the complexes showed cytotoxicity on human promyelocytic leukemia HL-60 cells with IC(50) values of the same order of magnitude as cisplatin. The interaction of the complexes with DNA was demonstrated by different techniques, suggesting that this biomolecule could be a potential target either in the parasites or in tumor cells., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We report the synthesis and characterization of several chiral salen- and salan-type ligands and their vanadium complexes, which are derived from salicylaldehyde or salicylaldehyde derivatives and chiral diamines (1R,2R-diaminocyclohexane, 1S,2S-diaminocyclohexane, and 1S,2S-diphenylethylenediamine). The structures of H(2)sal(R,R-chan)(2+) x 2 Cl(-) x (CH(3))(2)CHOH x H(2)O (1c; H(2)sal(R,R-chan) = N,N'-salicyl-R,R-cyclohexanediaminium), Etvan(S,S-chen) (3c; Etvan(S,S-chen) = N,N'-3-ethoxy-salicylidene-S,S-cyclohexanediiminato), and naph(R,R-chen) (6c; naph(R,R-chen) = N,N'-naphthylidene-R,R-cyclohexanediiminato) were determined by single-crystal X-ray diffraction. The corresponding vanadium(IV) complexes and several other new complexes involving different salicylaldehyde-type precursors were prepared and characterized in the solid state and in solution by spectroscopic techniques: UV-vis, circular dichroism, electron paramagnetic resonance, and (51)V NMR, which provide information on the coordination geometry. The salan complexes oxidize in organic solvents to V(V) species, and this process was also studied using spectroscopic techniques. Single crystals suitable for X-ray diffraction were obtained for [{V(V)O[sal(S,S-dpan)]}(2)(mu-O)] x H(2)O x 2(CH(3))(2)CHOH (14c; sal(S,S-dpan) = N,N'-salicyl-S,S-diphenylethylenediaminato) and [{V(V)O[t-Busal(R,R-chan)]}(2)(mu-O)] x 2 (CH(3))(2)CHOH (15c), both containing an OV(V)(mu-O)V(V)O moiety (V(2)O(3)(4+) core) with tetradentate ligands and one mu-oxo bridge. Both structures are the first examples of dinuclear vanadium complexes involving the V(V)(2)O(3)(4+) core with tetradentate ligands, the configuration of the V(2)O(3) unit being twist-angular. The V-salen and V-salan complexes are tested as catalysts in the oxidation of styrene, cyclohexene, cumene, and methyl phenyl sulfide with H(2)O(2) and t-BuOOH as oxidants. Overall, the V-salan complexes show higher activity and normally better selectivity in alkene oxidation and higher activity and enantioselectivity for sulfoxidation than their parent V-salen complexes, therefore being an advantageous alternative ligand system for oxidation catalysis. The better performance of V-salan complexes probably results from their significantly higher hydrolytic stability. Mechanisms for the alkene oxidation with these newly obtained V-salan compounds are discussed, including the use of DFT for the comparison of several alternative mechanisms for epoxidation.

The dipeptide and tripeptide analogues salicyl-L-aspartic acid (Sal-L-Asp) and salicylglycyl-L-aspartic acid (SalGly-L-Asp) were synthesized and their protonation and complex formation with V(IV)O2+ were studied in aqueous solution through the use of pH-potentiometry and spectroscopic (UV-Vis, CD and EPR) techniques. The phenolate terminus proved to be a good anchoring site to promote (i) the metal ion-induced deprotonation and subsequent coordination of the peptide amide group(s) in the pH range 4-5 for the dipeptide analogue, (ii) and in the pH range 5-6 in a very cooperative way for the tripeptide analogue. The results suggest that the presence of good anchoring donors on both sides of the amide groups is responsible for the cooperative deprotonation of the two amide-NH groups.