Hydrolysis, Ligand Exchange, and Redox Properties of Vanadium Compounds: Implications of Solution Transformation on Biological, Therapeutic, and Environmental Applications.

Vanadium is a transition metal with important industrial, technological, biological, and biomedical applications widespread in the environment and in living beings. The different reactions that vanadium compounds (VCs) undergo in the presence of proteins, nucleic acids, lipids and metabolites under mild physiological conditions are reviewed. In the environment vanadium is present naturally or through anthropogenic sources, the latter having an environmental impact caused by the dispersion of VCs in the atmosphere and aquifers.

Interaction of VO-hydrazonates with lysozyme.

Vanadium compounds (VCs) exhibit a broad range of pharmacological properties, with their most significant medical applications being in the treatment of cancer and diabetes. The therapeutic effects and mode of action of VCs may be associated with their ability to bind proteins and, consequently, understanding the VC-protein interaction is of paramount importance. Among the promising VCs, the VO complex with the aroylhydrazone furan-2-carboxylic acid ((3-ethoxy-2-hydroxybenzylidene)hydrazide, hereafter denoted as VC1), deserves attention, since it exhibits cytotoxicity against various cancer cell lines, including HeLa.

Exploiting the potential of rivastigmine-melatonin derivatives as multitarget metal-modulating drugs for neurodegenerative diseases.

The multifaceted nature of the neurodegenerative diseases, as Alzheimer's disease (AD) and Parkinson's disease (PD) with several interconnected etiologies, and the absence of effective drugs, led herein to the development and study of a series of multi-target directed ligands (MTDLs). The developed RIV-IND hybrids, derived from the conjugation of an approved anti-AD drug, rivastigmine (RIV), with melatonin analogues, namely indole (IND) derivatives, revealed multifunctional properties, by associating the cholinesterase inhibition of the RIV drug with antioxidant activity, biometal (Cu(II), Zn(II), Fe(III)) chelation properties, inhibition of amyloid-β (Aβ) aggregation (self- and Cu-induced) and of monoamine oxidases (MAOs), as well as neuroprotection capacity in cell models of AD and PD. In particular, two hybrids with hydroxyl-substituted indoles (5a2 and 5a3) could be promising multifunctional compounds that inspire further development of novel anti-neurodegenerative drugs.

Bridge vs Terminal Cyano-coordination in Binuclear Cobalt Porphyrin Dimers: Interplay of Electrons between Metal and Ligand and Spin-Coupling via Bridge.

Three cyano-coordinated cobalt porphyrin dimers were synthesized and thoroughly characterized. The X-ray structure of the complexes reveals that cyanide binds in a terminal fashion in both the and isomers of ethane- and ethylene-bridged cobalt porphyrin dimers, while in the ethylene-bridged dimer, cyanides bind in both terminal and bridging modes. The nonconjugated ethane-bridged complex stabilizes exclusively a diamagnetic metal-centered oxidation of type Co(por)(CN) both in the solid and in solution.

Protein-Protein Stabilization in VO/8-Hydroxyquinoline-Lysozyme Adducts.

The binding of the potential drug [VO(8-HQ)], where 8-HQ is 8-hydroxyquinolinato, with hen egg white lysozyme (HEWL) was evaluated through spectroscopic (electron paramagnetic resonance, EPR, and UV-visible), spectrometric (electrospray ionization-mass spectrometry, ESI-MS), crystallographic (X-ray diffraction, XRD), and computational (DFT and docking) studies. ESI-MS indicates the interaction of [VO(8-HQ)(HO)] and [VO(8-HQ)(HO)] species with HEWL. Room temperature EPR spectra suggest both covalent and non-covalent binding of the two different V-containing fragments.

Non-Covalent and Covalent Binding of New Mixed-Valence Cage-like Polyoxidovanadate Clusters to Lysozyme.

The high-resolution X-ray structures of the model protein lysozyme in the presence of the potential drug [VO(acetylacetonato)] from crystals grown in 1.1 M NaCl, 0.1 M sodium acetate at pH 4.

Experimental and Computational Studies on the Interaction of DNA with Hesperetin Schiff Base Cu Complexes.

The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or LH), isoniazid (HIN or LH), or thiosemicarbazide (HTSC or LH) and their Cu complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLH(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV-Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants () of the Cu compounds with CT-DNA, in the range (2.

Magnetic study and DFT analysis of a doubly carboxylato-bridged Co(II) derivative anchored with a 'scorpionate' precursor as a potential electrocatalyst for heterogeneous H evolution.

A new doubly carboxylato-bridged Co(II) dinuclear complex, [Co(bdtbpza)(NCS)] (1), was obtained in a satisfactory yield by employing a 'scorpionate'-type precursor, {bis-(3,5-di--butylpyrazol-1-yl)acetate}, and was then structurally characterized. Single-crystal X-ray diffraction analysis revealed that, in 1, each Co(II) is penta-coordinated, leading to a distorted trigonal-bipyramidal geometry within the coordination environment of NO. Weak antiferromagnetic coupling within the Co(II) ions in 1 was found based on the isotropic spin Hamiltonian = -(·) for the = 3/2 system.

Interaction with CT-DNA and in vitro cytotoxicity of two new copper(II)-based potential drugs derived from octanoic hydrazide ligands.

Two copper(II) complexes [Cu(Hpmoh)(NO)(NCS)] (1) and [Cu(peoh)(N)] (2) were designed and synthesized by reaction of Cu(NO)·3HO with hydrazone Schiff base ligands,abbreviated with Hpmoh and Hpeoh. Hpmoh and Hpeoh were prepared by condensation reaction of octanoic hydrazide with pyridine-2-carboxyaldehyde and 2-acetylpyridine, respectively. Complexes 1 and 2 were characterized using different analytical techniques such as FT-IR, UV-Vis, IR, EPR and single X-ray diffraction (XRD) analyses as well as computational methods (DFT).

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 entity of the type Co(por), while the other one is the ligand-centered oxidized entity of the type Co(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 complex.

Stabilization and Binding of [V O ] and Unprecedented [V O (NO )] to Lysozyme upon Loss of Ligands and Oxidation of the Potential Drug V O(acetylacetonato).

High-resolution crystal structures of lysozyme in the presence of the potential drug V O(acetylacetonato) under two different experimental conditions have been solved. The crystallographic study reveals the loss of the ligands, the oxidation of V to V and the subsequent formation of adducts of the protein with two different polyoxidovanadates: [V O ] , which interacts with lysozyme non-covalently, and the unprecedented [V O (NO )] , which is covalenty bound to the side chain of an aspartate residue of symmetry related molecules.

Stable Dication Diradicals of Triply Fused Metallo Chlorin-Porphyrin Heterodimers: Impact of the Bridge on the Control of Spin Coupling to Reactivity.

We report an unexpected rearrangement, controlled by the nature of the bridge, leading to the formation of novel, remarkably stable triply fused dinickel(II)/dicopper(II) chlorin-porphyrin dication diradical heterodimers in excellent yields. Here, a dipyrromethene bridge gets completely fused between two porphyrin macrocycles with two new C-C and one C-N bonds. The two macrocycles exhibit extensive π-conjugation through the bridge, which results in an antiferromagnetic coupling between the two π-cation radicals.

Implications of Protein Interaction in the Speciation of Potential VO-Pyridinone Drugs.

Vanadium complexes (VCs) are promising agents for the treatment, among others, of diabetes and cancer. The development of vanadium-based drugs is mainly limited by a scarce knowledge of the active species in the target organs, which is often determined by the interaction of VCs with biological macromolecules like proteins. Here, we have studied the binding of [VO(empp)] (where Hempp is 1-methyl-2-ethyl-3-hydroxy-4(1)-pyridinone), an antidiabetic and anticancer VC, with the model protein hen egg white lysozyme (HEWL) by electrospray ionization-mass spectrometry (ESI-MS), electron paramagnetic resonance (EPR), and X-ray crystallography.

A Series of Non-Oxido V Complexes of Dibasic ONS Donor Ligands: Solution Stability, Chemical Transformations, Protein Interactions, and Antiproliferative Activity.

A series of mononuclear non-oxido vanadium(IV) complexes, [V(L)] (), featuring tridentate bi-negative ONS chelating S-alkyl/aryl-substituted dithiocarbazate ligands HL, are reported. All the synthesized non-oxido V compounds are characterized by elemental analysis, spectroscopy (IR, UV-vis, and EPR), ESI-MS, as well as electrochemical techniques (cyclic voltammetry). Single-crystal X-ray diffraction studies of - reveal that the mononuclear non-oxido V complexes show distorted octahedral ( and ) or trigonal prismatic () arrangement around the non-oxido V center.

Promising anticancer agents based on 8-hydroxyquinoline hydrazone copper(II) complexes.

We report the synthesis and characterization of a group of benzoylhydrazones (L) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing distinct substituents (R = H, Cl, F, CH, OCH, OH and NH, for L, respectively; in L isonicotinohydrazide was used instead of benzylhydrazide). Cu(II) complexes were prepared by reaction of each benzoylhydrazone with Cu(II) acetate. All compounds were characterized by elemental analysis and mass spectrometry as well as by FTIR, UV-visible absorption, NMR or electron paramagnetic resonance spectroscopies.

Spectroscopic Characterization and Biological Activity of Hesperetin Schiff Bases and Their Cu(II) Complexes.

The three Schiff base ligands, derivatives of hesperetin, HHSB (-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]isonicotinohydrazide), HIN (-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]benzhydrazide) and HTSC (-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]thiosemicarbazide) and their copper complexes, CuHHSB, CuHIN, and CuHTSC were designed, synthesized and analyzed in terms of their spectral characterization and the genotoxic activity. Their structures were established using several methods: elemental analysis, FT-IR, UV-Vis, EPR, and ESI-MS. Spectral data showed that in the acetate complexes the tested Schiff bases act as neutral tridentate ligand coordinating to the copper ion through two oxygen (or oxygen and sulphur) donor atoms and a nitrogen donor atom.

Diheme cytochromes: Effect of mixed-axial ligation on the electronic structure and electrochemical properties with cobalt porphyrin dimer.

A series of six-coordinate diCo(III) porphyrin dimers, as synthetic analogues of diheme cytochromes, have been reported here having bis(imidazole), bis(pyridine) and mixed thiophenolate-pyridine/imidazole axial ligands. In the X-ray structures of bis(imidazole) and bis(pyridine) complexes, the axial ligands are in perpendicular orientation while they are parallelly oriented in their monomeric analog. The porphyrin rings are also highly ruffle-distorted in dimer but planar in monomer which reflect the effect of intramolecular interaction between two Co(porphyrin) units in dimers.

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 ML 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, ML, etc.) may interact with proteins.

Interaction with bioligands and in vitro cytotoxicity of a new dinuclear dioxido vanadium(V) complex.

One centrosymmetric bis(μ-oxido)-bridged vanadium(V) dimer with molecular formula [(VO)(pedf)] (1) has been synthesized from the reaction of VOSO·5HO with a Schiff base ligand (abbreviated with pedf) obtained from 2-acetylpyridine and 2-furoic hydrazide in methanol. Complex 1 was characterized by elemental analysis, UV-visible (UV-Vis), Fourier-transform infrared spectra (FT-IR), cyclic voltammetry (CV), electron paramagnetic resonance spectroscopy (EPR) and electrospray ionization-mass spectrometry (ESI-MS) techniques along with single crystal X-ray diffraction (SCXRD). The FT-IR spectral data of 1 indicated the involvement of oxygen and azomethine nitrogen in coordination to the central metal ion.

Solution chemical properties and anticancer potential of 8-hydroxyquinoline hydrazones and their oxidovanadium(IV) complexes.

We report the synthesis and characterization of a family of benzohydrazones (L, n = 1-6) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing different substituents in the para position. Their oxidovanadium(IV) complexes were prepared and compounds with 1:1 and 1:2 metal-to-ligand stoichiometry were obtained. All compounds were characterized by elemental analyses and mass spectrometry as well as FTIR, UV-visible absorption, NMR (ligand precursors) and EPR (complexes) spectroscopies, and by DFT computational methods.

Interaction of pharmacologically active pyrone and pyridinone vanadium(IV,V) complexes with cytochrome c.

The interaction between cytochrome c (Cyt) and potential vanadium drugs, formed by 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp) and maltolate (ma), was studied by ElectroSpray Ionization-Mass Spectrometry (ESI-MS). Since under physiological conditions redox processes are possible, the binding of the complexes in the oxidation state +IV and +V, [VO(dhp)], [VO(ma)], [VO(dhp)] and [VO(ma)], was examined. In all systems V-L-Cyt adducts are observed, their formation depending on V oxidation state, ligand L and metal concentration.

Highly Oxidized Cobalt Porphyrin Dimer: Control of Spin Coupling via a Bridge.

A cobalt porphyrin dimer is constructed in which two Co(II)porphyrins are connected covalently through a redox-active diethylpyrrole moiety via a flexible but "nonconjugated" methylene bridge. Upon oxidation with even a mild oxidant such as iodine, each cobalt(II) center and porphyrin ring undergo 1e oxidation, leading to the formation of a 4e-oxidized cobalt(III)porphyrin dication diradical complex. Other oxidants such as Cl and Br also produce similar results.

New mixed ligand oxidovanadium(IV) complexes: Solution behavior, protein interaction and cytotoxicity.

Herein we report the synthesis of five new mononuclear mixed ligand oxidovanadium(IV) complexes [VO(L)(L)] (1-5) with tridentate O,N,O-donor aroylhydrazones as main ligand (HL) and N,N-chelating 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) as co-ligand (L). The complexes were characterized by elemental and thermogravimetric analysis (TGA), IR, UV-vis, and electron paramagnetic resonance (EPR) spectroscopy, electrospray ionization-mass spectrometry (ESI-MS) and cyclic voltammetry (CV). The structure of 1-5 was confirmed by single crystal X-ray analysis and also optimized by density functional theory (DFT) methods.

Binding of V O , V OL, V OL and V O L Moieties to Proteins: X-ray/Theoretical Characterization and Biological Implications.

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 O and V OL , where L=2,2'-bipyridine or 1,10-phenanthroline (phen), and of trypsin with V O(picolinato) and V O (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.

Long-Range Intramolecular Spin Coupling through a Redox-Active Bridge upon Stepwise Oxidations: Control and Effect of Metal Ions.

Dinickel(II) and dicopper(II) porphyrin dimers have been constructed in which two metalloporphyrin units are widely separated by a long unconjugated dipyrrole bridge. Two macrocycles are aligned somewhat orthogonally to each other, while oxidation of the bridge generates a fully π-conjugated butterfly-like structure, which, in turn, upon stepwise oxidations by stronger oxidants result in the formation of the corresponding one- and two-electron-oxidized species exhibiting unusual long-range charge/radical delocalization to produce intense absorptions in the near-infrared (NIR) region and electron paramagnetic resonance (EPR) signals of a triplet state due to interaction between the unpaired spins on the Cu(II) ions. Although the two metal centers have a large physical separation through the bridge (more than 16 Å), they share electrons efficiently between them, behaving as a single unit rather than two independent centers.