Reversible Switching of Electronic Ground State in a Pentacoordinated Cu(II) 1D Cationic Polymer and Structural Diversity

Two copper­(II) polymeric complexes {[Cu­(HPymat)­(MeOH)]­(NO₃)}_<i>n</i> (<b>1</b>) and {[Cu₄(Pymab)₄­(H₂O)₄]­(NO₃)₄} (<b>2</b>) were synthesized with the carboxylate-containing Schiff-base ligands HPymat^– and Pymab^– [H₂Pymat = (<i>E</i>)-2-(1-(pyridin-2-yl)­methyleneamino)­terephthalic acid, HPymab = (<i>E</i>)-2-((pyridine-2-yl)­methyleneamino)­benzoic acid]. Complex <b>1</b> is a one-dimensional Cu­(II) cationic polymeric complex containing free protonated carboxylic groups and nitrate anions as counterions. Complex <b>2</b> is a zero-dimensional tetranuclear cationic Cu­(II) complex containing nitrate anions as counterions. Complex <b>1</b> shows rhombic electron paramagnetic resonance (EPR) spectra in the solid state at room temperature (RT) and 77 K and tetragonal EPR spectra in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) and “inverse” EPR spectrum in CH₃CN. Complex <b>2</b> shows rhombic EPR spectra in the solid state at RT and 77 K. But complex <b>2</b> shows tetragonal spectra in DMSO, DMF, and CH₃CN. Thermogravimetric analysis was also performed for both complexes <b>1</b> and <b>2</b>. Mean-square displacement amplitude analysis was carried out to detect librational disorder along the metal–ligand bonds in crystal structures

Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme

The interaction with proteins of metal-based drugs plays a crucial role in their transport, mechanism, and activity. For an active MLn complex, where L is the organic carrier, various binding modes (covalent and non-covalent, single or multiple) may occur and several metal moieties (M, ML, ML2, etc.) may interact with proteins. In this study, we have evaluated the interaction of [VIVO­(malt)2] (bis­(maltolato)­oxidovanadium­(IV) or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2-methyl-4H-pyran-4-onato) with the model protein hen egg white lysozyme (HEWL) by electrospray ionization mass spectrometry, electron paramagnetic resonance, and X-ray crystallography. The multiple binding of different V-containing isomers and enantiomers to different sites of HEWL is observed. The data indicate both non-covalent binding of cis-[VO­(malt)2(H2O)] and [VO­(malt)­(H2O)3]+ and covalent binding of [VO­(H2O)3–4]2+ and cis-[VO­(malt)2] and other V-containing fragments to the side chains of Glu35, Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate. Our results suggest that the multiple and variable interactions of potential VIVOL2 drugs with proteins can help to better understand their solution chemistry and contribute to define the molecular basis of the mechanism of action of these intriguing molecules

Nonoxido V^IV Complexes: Prediction of the EPR Spectrum and Electronic Structure of Simple Coordination Compounds and Amavadin

Density functional theory (DFT) calculations of the ⁵¹V hyperfine coupling (HFC) tensor <b>A</b> have been completed for 20 “bare” V^IV complexes with different donor sets, electric charges, and coordination geometries. Calculations were performed with ORCA and Gaussian software, using functionals BP86, TPSS0, B1LYP, PBE0, B3LYP, B3P, B3PW, O3LYP, BHandHLYP, BHandH, and B2PLYP. Among the basis sets, 6-311g­(d,p), 6-311++g­(d,p), VTZ, cc-pVTZ, def2-TZVPP, and the “core properties” CP­(PPP) were tested. The experimental <i>A</i>_iso and <i>A</i>_<i>i</i> (where <i>i</i> = <i>x</i> or <i>z</i>, depending on the geometry and electronic structure of V^IV complex) were compared with the values calculated by DFT methods. The results indicated that, based on the mean absolute percentage deviation (MAPD), the best functional to predict <i>A</i>_iso or <i>A_i</i> is the double hybrid B2PLYP. With this functional and the basis set VTZ, it is possible to predict the <i>A</i>_iso and <i>A</i>_<i>z</i> of the EPR spectrum of amavadin with deviations of −1.1% and −2.0% from the experimental values. The results allowed us to divide the spectra of nonoxido V^IV compounds in three typescalled “type 1”, “type 2”, and “type 3”, characterized by different composition of the singly occupied molecular orbital (SOMO) and relationship between the values of <i>A</i>_<i>x</i>, <i>A</i>_<i>y</i>, and <i>A</i>_<i>z</i>. For “type 1” spectra, <i>A</i>_<i>z</i> ≫ <i>A</i>_<i>x</i> ≈ <i>A</i>_<i>y</i> and <i>A</i>_<i>z</i> is in the range of (135–155) × 10^–4 cm^–1; for “type 2” spectra, <i>A</i>_<i>x</i> ≈ <i>A</i>_<i>y</i> ≫ <i>A</i>_<i>z</i> and <i>A</i>_<i>x</i> ≈ <i>A</i>_<i>y</i> are in the range of (90–120) × 10^–4 cm^–1; and for the intermediate spectra of “type 3”, <i>A</i>_<i>z</i> > <i>A</i>_<i>y</i> > <i>A</i>_<i>x</i> or <i>A</i>_<i>x</i> > <i>A</i>_<i>y</i> > <i>A</i>_<i>z</i>, with <i>A</i>_<i>z</i> or <i>A</i>_<i>x</i> values in the range of (120–135) × 10^–4 cm^–1. The electronic structure of the V^IV species was also discussed, and the results showed that the values of <i>A</i>_<i>x</i> or <i>A</i>_<i>z</i> are correlated with the percent contribution of V-d_<i>xy</i> orbital in the SOMO. Similarly to V^IVO species, for amavadin the SOMO is based mainly on the V-d_<i>xy</i> orbital, and this accounts for the large experimental value of <i>A</i>_<i>z</i> (153 × 10^–4 cm^–1)

Formation of New Non-oxido Vanadium(IV) Species in Aqueous Solution and in the Solid State by Tridentate (O, N, O) Ligands and Rationalization of Their EPR Behavior

The systems formed by the V^IVO²⁺ ion with tridentate ligands provided with the (O, N_imine, O) donor set were described. The ligands studied were 2,2′-dihydroxyazobenzene (Hdhab), α-(2-hydroxy-5-methylphenylimino)-<i>o</i>-cresol (Hhmpic), calmagite (H₂calm), anthracene chrome red A (H₃anth), calcon (H₂calc), and calconcarboxylic acid (H₃calc^C). They can bind vanadium with the two deprotonated phenol groups and the imine nitrogen to give (5,6)-membered chelate rings. The systems were studied with EPR, UV–vis and IR spectroscopy, pH-potentiometry, and DFT methods. The ligands form unusual non-oxido V^IV compounds both in aqueous solution and in the solid state. [V­(anthH_–1)₂]^4– and [V­(calmH_–1)₂]^2– (formed in water at the physiological pH) and [V­(dhabH_–1)₂] and [V­(hmpicH_–1)₂] (formed in the solid state in MeOH) are hexa-coordinated with geometry intermediate between the octahedron and the trigonal prism and an <i>unsymmetric facial</i> arrangement of the two ligand molecules. DFT calculations were used to predict the structure and ⁵¹V hyperfine coupling tensor <b>A</b> of the non-oxido species. The EPR behavior of 13 non-oxido V^IV species was put into relationship with the relevant geometrical parameters and was rationalized in terms of the spin density on the d_<i>xy</i> orbital. Depending on the geometric isomer formed (<i>meridional</i> or <i>facial</i>), d_<i>z</i>² mixes with the d_<i>xy</i> orbital, and this effect causes the lowering of the highest ⁵¹V <i>A</i> value

V^IVO Versus V^IV Complex Formation by Tridentate (O, N_arom, O) Ligands: Prediction of Geometry, EPR ⁵¹V Hyperfine Coupling Constants, and UV–Vis Spectra

Systems formed using the V^IVO²⁺ ion with tridentate ligands containing a (O, N_arom, O) donor set were described. Examined ligands were 3,5-bis­(2-hydroxyphenyl)-1-phenyl-1<i>H</i>-1,2,4-triazole (H₂hyph^Ph), 4-[3,5-bis­(2-hydroxyphenyl)-1<i>H</i>-1,2,4-triazol-1-yl]­benzoic acid (H₃hyph^C), 4-[3,5-bis­(2-hydroxyphenyl)-1<i>H</i>-1,2,4-triazol-1-yl]­benzenesulfonic acid (H₃hyph^S), and 2,6-bis­(2-hydroxyphenyl)­pyridine (H₂bhpp), with H₃hyph^C being an orally active iron chelator that is commercially available under the name Exjade (Novartis) for treatment of chronic iron overload arising from blood transfusions. The systems were studied using EPR, UV–Vis, and IR spectroscopies, pH potentiometry, and DFT methods. The ligands bind vanadium with the two terminal deprotonated phenol groups and the central aromatic nitrogen to give six-membered chelate rings. In aqueous solution the main species were the mono- and bis-chelated V^IVO complexes, whereas in the solid state neutral non-oxido V^IV compounds were formed. [V­(hyph^Ph)₂] and [V­(bhpp)₂] are hexacoordinated, with a geometry close to the octahedral and a meridional arrangement of the ligands. DFT calculations allow distinguishing V^IVO and V^IV species and predicting their structure, the ⁵¹V hyperfine coupling constant tensor <i><b>A</b></i>, and the electronic absorption spectra. Finally, EPR spectra of several non-oxido V^IV species were compared using relevant geometrical parameters to demonstrate that in the case of tridentate ligands the ⁵¹V hyperfine coupling constant is related to the geometric isomerism (meridional or facial) rather than the twist angle Φ, which measures the distortion of the hexacoordinated structure toward a trigonal prism

Metal vs Ligand Oxidation: Coexistence of Both Metal-Centered and Ligand-Centered Oxidized Species

A series of two-electron-oxidized cobalt porphyrin dimers have been synthesized upon controlled oxidations using halogens. Rather unexpectedly, X-ray structures of two of these complexes contain two structurally different low-spin molecules in the same asymmetric unit of their unit cells: one is the metal-centered oxidized diamagnetic entity of the type CoIII(por), while the other one is the ligand-centered oxidized paramagnetic entity of the type CoII(por•+). Spectroscopic, magnetic, and DFT investigations confirmed the coexistence of the two very different electronic structures both in the solid and solution phases and also revealed a ferromagnetic spin coupling between Co­(II) and porphyrin π-cation radicals and a weak antiferromagnetic coupling between the π-cation radicals of two macrocycles via the bridge in the paramagnetic complex

Decoding Surface Interaction of V^IVO Metallodrug Candidates with Lysozyme

The interaction of metallodrugs with proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various V^IVO compounds with lysozyme, a prototypical model of protein receptor. Five V^IVO-flavonoid drug candidates formed by quercetin (que), morin (mor), 7,8-dihydroxyflavone (7,8-dhf), chrysin (chr), and 5-hydroxyflavone (5-hf)effective against several osteosarcoma cell linesand two benchmark V^IVO species of acetylacetone (acac) and catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL₂] and the surface residues of lysozyme. The qualitative strength of the interaction from EPR is [VO­(que)₂]^2– ≈ [VO­(mor)₂] > [VO­(7,8-dhf)₂]^2– > [VO­(chr)₂] ≈ [VO­(5-hf)₂] > [VO­(acac)₂] ≈ [VO­(cat)₂]^2–. This observation is compared with protein-<i>ligand</i> docking calculations with GOLD software examining the GoldScore scoring function (<i>F</i>), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the <i>F</i>_max value and depends on the number of OH or CO groups of the ligands that can interact with different sites on the protein surface and, more particularly, with those in the vicinity of the active site of the enzyme. The interaction strength determines the type of signal revealed (<i>rigid limit</i>, <i>slow tumbling</i>, or <i>isotropic</i>) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic metal species with a generic protein

Nonoxido Vanadium(IV) Compounds Involving Dithiocarbazate-Based Tridentate ONS Ligands: Synthesis, Electronic and Molecular Structure, Spectroscopic and Redox Properties

A new series of nonoxido vanadium­(IV) compounds [VL₂] (L = L¹–L³) (<b>1</b>–<b>3</b>) have been synthesized using dithiocarbazate-based tridentate Schiff-base ligands H₂L¹–H₂L³, containing an appended phenol ring with a <i>tert</i>-butyl substitution at the 2-position. The compounds are characterized by X-ray diffraction analysis (<b>1</b>, <b>3</b>), IR, UV-vis, EPR spectroscopy, and electrochemical methods. These are nonoxido V^IV complexes that reveal a rare distorted trigonal prismatic arrangement around the “bare” vanadium centers. Concerning the ligand isomerism, the structure of <b>1</b> and <b>3</b> can be described as intermediate between <i>mer</i> and <i>sym-fac</i> isomers. DFT methods were used to predict the geometry, <b>g</b> and ⁵¹V <b>A</b> tensors, electronic structure, and electronic absorption spectrum of compounds <b>1</b>–<b>3</b>. Hyperfine coupling constants measured in the EPR spectra can be reproduced satisfactorily at the level of theory PBE0/VTZ, whereas the wavelength and intensity of the absorptions in the UV-vis spectra at the level CAM-B3LYP/gen, where “gen” is a general basis set obtained using 6-31+g­(d) for S and 6-31g for all the other elements. The results suggest that the electronic structure of <b>1</b>–<b>3</b> can be described in terms of a mixing among V-<i>d</i>_<i>xy</i>, V-<i>d</i>_<i>xz</i>, and V-<i>d</i>_<i>yz</i> orbitals in the singly occupied molecular orbital (SOMO), which causes a significant lowering of the absolute value of the ⁵¹V hyperfine coupling constant along the <i>x</i>-axis. The cyclic voltammograms of these compounds in dichloroethane solution display three one-electron processes, two in the cathodic and one in the anodic potential range. Process A (<i>E</i>_1/2 = +1.06 V) is due to the quasi-reversible V­(IV/V) oxidation while process B at <i>E</i>_1/2 = −0.085 V is due to the quasi-reversible V­(IV/III) reduction, and the third one (process C) at a more negative potential <i>E</i>_1/2 = −1.66 V is due to a ligand centered reduction, all potentials being measured vs Ag/AgCl reference

Elucidation of Binding Site and Chiral Specificity of Oxidovanadium Drugs with Lysozyme through Theoretical Calculations

This study presents an implementation of the protein–ligand docking program GOLD and a generalizable method to predict the binding site and orientation of potential vanadium drugs. Particularly, theoretical methods were applied to the study of the interaction of two V^IVO complexes with antidiabetic activity, [V^IVO­(pic)₂(H₂O)] and [V^IVO­(ma)₂(H₂O)], where pic is picolinate and ma is maltolate, with lysozyme (Lyz) for which electron paramagnetic resonance spectroscopy suggests the binding of the moieties VO­(pic)₂ and VO­(ma)₂ through a carboxylate group of an amino acid residue (Asp or Glu). The work is divided in three parts: (1) the generation of a new series of parameters in GOLD program for vanadium compounds and the validation of the method on five X-ray structures of V^IVO and V^V species bound to proteins; (2) the prediction of the binding site and enantiomeric preference of [VO­(pic)₂(H₂O)] to lysozyme, for which the X-ray diffraction analysis displays the interaction of a unique isomer (i.e., OC-6–23-Δ) through Asp52 residue, and the subsequent refinement of the results with quantum mechanics/molecular mechanics methods; (3) the application of the same approach to the interaction of [VO­(ma)₂(H₂O)] with lysozyme. The results show that convenient implementation of protein–ligand docking programs allows for satisfactorily reproducing X-ray structures of metal complexes that interact with only one coordination site with proteins and predicting with blind procedures relevant low-energy binding modes. The results also demonstrate that the combination of docking methods with spectroscopic data could represent a new tool to predict (metal complex)–protein interactions and have a general applicability in this field, including for paramagnetic species

Synthesis and Characterization of V^IVO Complexes of Picolinate and Pyrazine Derivatives. Behavior in the Solid State and Aqueous Solution and Biotransformation in the Presence of Blood Plasma Proteins

Oxidovanadium­(IV) complexes with 5-cyanopyridine-2-carboxylic acid (HpicCN), 3,5-difluoropyridine-2-carboxylic acid (HpicFF), 3-hydroxypyridine-2-carboxylic acid (H₂hypic), and pyrazine-2-carboxylic acid (Hprz) have been synthesized and characterized in the solid state and aqueous solution through elemental analysis, IR and EPR spectroscopy, potentiometric titrations, and DFT simulations. The crystal structures of the complexes (<i>OC</i>-6-23)-[VO­(picCN)₂(H₂O)]·2H₂O (<b>1</b>·2H₂O), (<i>OC</i>-6-24)-[VO­(picCN)₂(H₂O)]·4H₂O (<b>2</b>·4H₂O), (<i>OC</i>-6-24)-Na­[VO­(Hhypic)₃]·H₂O (<b>4</b>), and two enantiomers of (<i>OC</i>-6-24)-[VO­(prz)₂(H₂O)] (Λ-<b>5</b> and Δ-<b>5</b>) have been determined also by X-ray crystallography. <b>1</b> presents the first crystallographic evidence for the formation of a <i>OC</i>-6-23 isomer for bis­(picolinato) V^IVO complexes, whereas <b>2</b>, <b>4</b>, and <b>5</b> possess the more common <i>OC</i>-6-24 arrangement. The strength order of the ligands is H₂hypic ≫ HpicCN > Hprz > HpicFF, and this results in a different behavior at pH 7.40. In organic and aqueous solution the three isomers <i>OC</i>-6-23, <i>OC</i>-6-24, and <i>OC</i>-6-42 are formed, and this is confirmed by DFT simulations. In all the systems with apo-transferrin (VO)₂(apo-hTf) is the main species in solution, with the hydrolytic V^IVO species becoming more important with lowering the strength of the ligand. In the systems with albumin, (VO)_<i>x</i>HSA (<i>x</i> = 5, 6) coexists with VOL₂(HSA) and VOL­(HSA)­(H₂O) when L = picCN, prz, with [VO­(Hhypic)­(hypic)]⁻, [VO­(hypic)₂]^2–, and [(VO)₄(μ-hypic)₄(H₂O)₄] when H₂hypic is studied, and with the hydrolytic V^IVO species when HpicFF is examined. Finally, the consequence of the hydrolysis on the binding of V^IVO²⁺ to the blood proteins, the possible uptake of V species by the cells, and the possible relationship with the insulin-enhancing activity are discussed