Exploring the Antitumor Efficacy of N-Heterocyclic Nitrilotriacetate Oxidovanadium(IV) Salts on Prostate and Breast Cancer Cells.

The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(H2O)](H2O)2 (I) and [(acr)H][VO(nta)(H2O)](H2O)2 (II), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts-1,10-phenanthrolinium, [(phen)H][VO(nta)(H2O)](H2O)0.5 (III), 2,2'-bipyridinium [(bpy)H][VO(nta)(H2O)](H2O) (IV), and two newly synthesized compounds (I) and (II)-were evaluated against prostate cancer (PC3) and breast cancer (MCF-7) cells. All the compounds exhibited strong cytotoxic effects on cancer cells and normal cells (HaCaT human keratinocytes). The structure-activity relationship analysis revealed that the number and arrangement of conjugated aromatic rings in the counterion had an impact on the antitumor effect. The compound (III), the 1,10-phenanthrolinium analogue, exhibited the greatest activity, whereas the acridinium salt (II), with a different arrangement of three conjugated aromatic rings, showed the lowest toxicity. The increased concentrations of the compounds resulted in alterations to the cell cycle distribution with different effects in MCF-7 and PC3 cells. In MCF-7 cells, compounds I and II were observed to block the G2/M phase, while compounds III and IV were found to arrest the cell cycle in the G0/G1 phase. In PC3 cells, all compounds increased the rates of cells in the G0/G1 phase.

Vanadium Compounds with Antidiabetic Potential.

Over the last four decades, vanadium compounds have been extensively studied as potential antidiabetic drugs. With the present review, we aim at presenting a general overview of the most promising compounds and the main results obtained with in vivo studies, reported from 1899-2023. The chemistry of vanadium is explored, discussing the importance of the structure and biochemistry of vanadate and the impact of its similarity with phosphate on the antidiabetic effect. The spectroscopic characterization of vanadium compounds is discussed, particularly magnetic resonance methodologies, emphasizing its relevance for understanding species activity, speciation, and interaction with biological membranes. Finally, the most relevant studies regarding the use of vanadium compounds to treat diabetes are summarized, considering both animal models and human clinical trials. An overview of the main hypotheses explaining the biological activity of these compounds is presented, particularly the most accepted pathway involving vanadium interaction with phosphatase and kinase enzymes involved in the insulin signaling cascade. From our point of view, the major discoveries regarding the pharmacological action of this family of compounds are not yet fully understood. Thus, we still believe that vanadium presents the potential to help in metabolic control and the clinical management of diabetes, either as an insulin-like drug or as an insulin adjuvant. We look forward to the next forty years of research in this field, aiming to discover a vanadium compound with the desired therapeutic properties.

Interaction of Vanadium Complexes with Proteins: Revisiting the Reported Structures in the Protein Data Bank (PDB) since 2015.

The structural determination and characterization of molecules, namely proteins and enzymes, is crucial to gaining a better understanding of their role in different chemical and biological processes. The continuous technical developments in the experimental and computational resources of X-ray diffraction (XRD) and, more recently, cryogenic Electron Microscopy (cryo-EM) led to an enormous growth in the number of structures deposited in the Protein Data Bank (PDB). Bioinorganic chemistry arose as a relevant discipline in biology and therapeutics, with a massive number of studies reporting the effects of metal complexes on biological systems, with vanadium complexes being one of the relevant systems addressed. In this review, we focus on the interactions of vanadium compounds (VCs) with proteins. Several types of binding are established between VCs and proteins/enzymes. Considering that the V-species that bind may differ from those initially added, the mentioned structural techniques are pivotal to clarifying the nature and variety of interactions of VCs with proteins and to proposing the mechanisms involved either in enzymatic inhibition or catalysis. As such, we provide an account of the available structural information of VCs bound to proteins obtained by both XRD and/or cryo-EM, mainly exploring the more recent structures, particularly those containing organic-based vanadium complexes.

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications.

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the in vitro studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.g. vanadium antidiabetic complexes at the physiological level, providing clues of their mechanism of action. The present article carries out a bibliographical research emphaticizing the chemical speciation of the vanadium with different amino acids and reviewing also some other important aspects such as its chemistry and therapeutical applications of several vanadium complexes.

VOSalophen: a vanadium complex with a stilbene derivative-induction of apoptosis, autophagy, and efficiency in experimental cutaneous leishmaniasis.

In our previous work, we demonstrated the promising in vitro effect of VOSalophen, a vanadium complex with a stilbene derivative, against Leishmania amazonensis. Its antileishmanial activity has been associated with oxidative stress in L. amazonensis promastigotes and L. amazonensis-infected macrophages. In the present study, the mechanism involved in the death of parasites after treatment with VOSalophen, as well as in vivo effect in the murine model cutaneous leishmaniasis, has been investigated. Promastigotes of L. amazonensis treated with VOSalophen presented apoptotic cells features, such as cell volume decrease, phosphatidylserine externalization, and DNA fragmentation. An increase in autophagic vacuoles formation in treated promastigotes was also observed, showing that autophagy also may be involved in the death of these parasites. In intracellular amastigotes, DNA fragmentation was observed after treatment with VOSalophen, but this effect was not observed in host cells, highlighting the selective effect of this vanadium complex. In addition, VOSalophen showed activity in the murine model of cutaneous leishmaniasis, without hepatic and renal damages. The outcome described here points out that VOSalophen had promising antileishmanial properties and these data also contribute to the understanding of the mechanisms involved in the death of protozoa induced by metal complexes.

A refreshing approach to understanding the action on DNA of vanadium (IV) and (V) complexes derived from the anticancer VCp2Cl2.

A computational study based on derivatives of the anticancer VCp2Cl2 compound and their interaction with representative models of deoxyribonucleic acid (DNA) is presented. The derivatives were obtained by substituting the cyclopentadienes of VCp2Cl2 with H2O, NH3, OH-, Cl-, O2- and C2O42- ligands. The oxidation states IV and V of vanadium were considered, so a total of 20 derivative complexes are included. The complexes interactions with DNA were studied using two different models, the first model considers the interactions of the complexes with the pair Guanine-Cytosine (G-C) and the second involves the interaction of the complexes with adjacent pairs, that is, d(GG). This study compares methodologies based on density functional theory with coupled cluster like calculations (DLPNO-CCSD(T)), the gold standard of electronic structure methods. Furthermore, the change in the electron density of the hydrogen bonds that keep bonded the G-C pair and d(GG) pairs, due to the presence of vanadium (IV) and (V) complexes is rationalize. To this aim, quantities obtained from the topology of the electron densities are inspected, particularly the value of the electron density at the hydrogen bond critical points. The approach allowed to identify vanadium complexes that lead to significant changes in the hydrogen bonds indicated above, a key aspect in the understanding, development, and proposal of mechanisms of action between metal complexes and DNA.

Vanadium Complexes with Thioanilide Derivatives of Amino Acids: Inhibition of Human Phosphatases and Specificity in Various Cell Models of Metabolic Disturbances.

In the text, the synthesis and characteristics of the novel ONS-type vanadium (V) complexes with thioanilide derivatives of amino acids are described. They showed the inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1, and SHP2) in the submicromolar range, as well as the inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxidovanadium(IV) (BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, including also glucose utilizatiand ONO Complexes are Inhibitors ofon in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.

(OC-6-13)-difluoridooxidobis(propan-2-ol)(propan-2-olato)vanadium(V).

The distorted octahedral title complex, [V(V)(C3H7O)(C3H8O)2F2O], was synthesized via ligand exchange at [V(V)O(OiPr)3] with aqueous hydrogen fluoride in propan-2-ol and crystallized from (D)chloroform at 238 K after a few weeks. Crystal structure determination shows two C1-symmetric moieties to be present in the asymmetric unit, forming infinite chains along [100] via hydrogen bonds. The compound provides the first crystal structure containing the [VF2O(OiPr)] motif.

Molecular modeling of [VO(L1-4)(R)] complexes (R = bipyridine, phenanthroline): DFT study of antioxidant activity, DNA binding and evaluation of electron-donating and -withdrawing substituent groups.

A DFT (density functional theory) study was conducted with eight oxovanadium complexes (C1 - C8) of general formula [VO(L1-4)(R)] (R = bipyridine, phenanthroline; L1-4 = group of ligands derived from dithiocarbamate). The obtained geometries showed a good correlation with the experimental structures. Molecular orbital analysis revealed that the contribution of the L-ligand in the SOMO (single-occupied molecular orbital) of the complexes correlated with the experimental antioxidant activity (IC50), while the contribution of the R-ligand to the LUMO (lowest unoccupied molecular orbital) of the complexes correlated with the experimental complex-DNA interaction (Kb). It has been identified that the presence of an electron-donating substituent group (such as -NH2) in the C5 - C6 structures should enhance these complexes' antioxidant and DNA interaction activities.

Repurposing Therapeutic Drugs Complexed to Vanadium in Cancer.

Repurposing drugs by uncovering new indications for approved drugs accelerates the process of establishing new treatments and reduces the high costs of drug discovery and development. Metal complexes with clinically approved drugs allow further opportunities in cancer therapy-many vanadium compounds have previously shown antitumor effects, which makes vanadium a suitable metal to complex with therapeutic drugs, potentially improving their efficacy in cancer treatment. In this review, covering the last 25 years of research in the field, we identified non-oncology-approved drugs suitable as ligands to obtain different vanadium complexes. Metformin-decavanadate, vanadium-bisphosphonates, vanadyl(IV) complexes with non-steroidal anti-inflammatory drugs, and cetirizine and imidazole-based oxidovanadium(IV) complexes, each has a parent drug known to have different medicinal properties and therapeutic indications, and all showed potential as novel anticancer treatments. Nevertheless, the precise mechanisms of action for these vanadium compounds against cancer are still not fully understood.

MD Simulations to Calculate NMR Relaxation Parameters of Vanadium(IV) Complexes: A Promising Diagnostic Tool for Cancer and Alzheimer's Disease.

Early phase diagnosis of human diseases has still been a challenge in the medicinal field, and one of the efficient non-invasive techniques that is vastly used for this purpose is magnetic resonance imaging (MRI). MRI is able to detect a wide range of diseases and conditions, including nervous system disorders and cancer, and uses the principles of NMR relaxation to generate detailed internal images of the body. For such investigation, different metal complexes have been studied as potential MRI contrast agents. With this in mind, this work aims to investigate two systems containing the vanadium complexes [VO(metf)2]·H2O (VC1) and [VO(bpy)2Cl]+ (VC2), being metformin and bipyridine ligands of the respective complexes, with the biological targets AMPK and ULK1. These biomolecules are involved in the progression of Alzheimer's disease and triple-negative breast cancer, respectively, and may act as promising spectroscopic probes for detection of these diseases. To initially evaluate the behavior of the studied ligands within the aforementioned protein active sites and aqueous environment, four classical molecular dynamics (MD) simulations including VC1 + H2O (1), VC2 + H2O (2), VC1 + AMPK + H2O (3), and VC2 + ULK1 + H2O (4) were performed. From this, it was obtained that for both systems containing VCs and water only, the theoretical calculations implied a higher efficiency when compared with DOTAREM, a famous commercially available contrast agent for MRI. This result is maintained when evaluating the system containing VC1 + AMPK + H2O. Nevertheless, for the system VC2 + ULK1 + H2O, there was observed a decrease in the vanadium complex efficiency due to the presence of a relevant steric hindrance. Despite that, due to the nature of the interaction between VC2 and ULK1, and the nature of its ligands, the study gives an insight that some modifications on VC2 structure might improve its efficiency as an MRI probe.

Enzyme PTP-1B Inhibition Studies by Vanadium Metal Complexes: a Kinetic Approach.

The medical field now needs more novel drugs to treat obesity and type-2 diabetes mellitus (T2D) than ever before. Obesity and T2D are both characterized by resistance to the hormones leptin and insulin. PTP-1B is a promising target for drug growth, as strong genetic, pharmacological, and biochemical evidence points to the possibility of treating diabetes and obesity by blocking the PTP-1B enzyme. Studies have also found that PTP-1B is overexpressed in patients with diabetes and obesity, suggesting that inhibiting PTP-1B may be a useful technique in their care. There are no clinically used PTP-1B inhibitors, despite the fact that numerous naturally occurring PTP-1B inhibitors have demonstrated great therapeutic promise. This is most likely due to their low activity or lack of selectivity. It is still important to look for more effective and focused PTP-1B inhibitors. A few organovanadium metal complexes were synthesized and characterized, and binding studies on vanadium complexes with PTP-B were also performed using fluorescence emission spectroscopy. Additionally, we theoretically (molecular modeling) and experimentally (enzyme kinetics) examined the PTP-1B inhibitory effects of these vanadium metal complexes and found that they have excellent PTP-1B inhibitory properties.

New oxovanadium(IV) complexes overcame drug resistance and increased in vitro cytotoxicity by an apoptotic pathway in breast cancer cells.

In order to examine the anticancer potential of oxovanadium(IV) complexes with thiosemicarbazone, two new complexes were prepared starting from 2-thenoyltrifluoroacetone-S-methylthiosemicarbazone. The complexes with tetradentate thiosemicarbazone ligand were characterized by elemental analysis, IR, ESI MS, and single-crystal X-ray diffraction analysis. Cytotoxicity on breast cancer cells, MDA-MB-231 and MCF-7, was determined by MTT assay. Cisplatin was positive control and the results were compared with those of the normal cells, HUVEC and 3T3. The complexes exhibited greater activity on cancer cells than cisplatin, but they were cytotoxic at several times higher concentrations in the healthy cells. In our study, the presence of thiophene and fluoro groups in the oxovanadium(IV) complexes with thiosemicarbazone increased greatly the cytotoxic activity of the complexes on breast cancer cells. Moreover, the complexes induced apoptosis-mediated cell death and also reduced the expression of MDR-1 or P-glycoprotein and ABCG2. As a result, the findings indicated that the complexes have selective cytotoxicity on breast cancer cells and can overcome multidrug resistance. These properties of the complexes make it possible to be a potential anticancer drug candidate for breast cancer treatment.

The Influence of Organic Vanadium Complexes on an Antioxidant Profile in Adipose Tissue in Wistar Rats.

One of the aspects of biological activity of vanadium is its influence on carbohydrate metabolism. For more than 30 years, various vanadium complexes have been tested as antidiabetic agents. This study researched organic vanadium complexes with bipyridinium ligands and their influences on metabolic rate, as well as on the antioxidant activity of adipose tissue. The effects of sodium (2,2'-bipyridine) oxidobisperoxovanadate (V) octahydrate (known as the V complex), bis(2,2'-bipyridine) oxidovanadium (IV) sulfate dehydrate (known as the B complex), and bis(4.4'-dimethyl-2,2'-bipyridine) oxidovanadium (IV) sulfate dihydrate (labelled as the BM complex) were assessed. Solutions of the tested complexes were introduced intraperitoneally with a probe to animals fed with either a control diet or a high-fat diet. The BM complex had a significant influence on the increase in ferric reducing antioxidant power, as well as on the concentration of glutathione in the adipose tissue of rats fed with a high-fat diet. The V complex increased the concentration of glutathione in the adipose tissue of rats fed with control fodder, as well as significantly reduced the relative change in rat weight for the high-fat diet. Furthermore, the presence of each tested vanadium complex had an impact of statistically significant increase in basal metabolic rate, regardless of applied diet. Further research on these organic vanadium complexes is necessary to understand the mechanisms responsible for their ability to affect adipose tissue.

Understanding the Potential In Vitro Modes of Action of Bis(ß-diketonato) Oxovanadium(IV) Complexes.

To understand the potential in vitro modes of action of bis(ß-diketonato) oxovanadium(IV) complexes, nine compounds of varying functionality have been screened using a range of biological techniques. The antiproliferative activity against a range of cancerous and normal cell lines has been determined, and show these complexes are particularly sensitive against the lung carcinoma cell line, A549. Annexin V (apoptosis) and Caspase-3/7 assays were studied to confirm these complexes induce programmed cell death. While gel electrophoresis was used to determine DNA cleavage activity and production of reactive oxygen species (ROS), the Comet assay was used to determine induced genomic DNA damage. Additionally, Förster resonance energy transfer (FRET)-based DNA melting and fluorescent intercalation displacement assays have been used to determine the interaction of the complexes with double strand (DS) DNA and to establish preferential DNA base-pair binding (AT versus GC).

2'-3'-Cyclic Nucleotide 3'-Phosphodiesterase Inhibition by Organometallic Vanadium Complexes: A Potential New Paradigm for Studying CNS Degeneration.

The enzyme, 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) has been known for over fifty years. Nevertheless, the roles this membrane-bound enzyme play have yet to be described completely. Recently, there has been renewed interest in the study of this enzyme due to studies that suggest that CNPase plays a role in the mediation of cellular inflammatory responses in renal and nervous system tissues. Also, this enzyme, found in oligodendrocytes of the nervous system, has been reported to participate in significant regulatory changes associated with age which may be involved in age-related CNS degeneration. Consequently, development of CNPase inhibitors is of interest and should aid in the study of this, as yet, poorly understood enzyme. In this work we utilized a spectrophotometric enzyme assay to determine the effect a panel of organo-vanadium complexes had on isolated hamster myelin CNPase activity. Our group has now identified several potent in vitro CNPase inhibitors that could prove useful in clarifying the important roles of this enzyme.

Therapeutic potential of vanadium complexes with 1,10-phenanthroline ligands, quo vadis? Fate of complexes in cell media and cancer cells.

VIVO-complexes formulated as [VIVO(OSO3)(phen)2] (1) (phen = 1,10-phenanthroline), [VIVO(OSO3)(Me2phen)2] (2) (Me2phen = 4,7-dimethyl-1,10-phenanthroline) and [VIVO(OSO3)(amphen)2] (3) (amphen = 5-amino-1,10-phenanthroline) were prepared and stability in cell incubation media evaluated. Their cytotoxicity was determined against the A2780 (ovarian), MCF7 (breast) and PC3 (prostate) human cancer cells at different incubation times. While at 3 and 24 h the cytotoxicity differs for complexes and corresponding free ligands, at 72 h incubation all compounds are equally active presenting low IC50 values. Upon incubation of A2780 cells with 1-3, cellular distribution of vanadium in cytosol, membranes, nucleus and cytoskeleton, indicate that the uptake of V is low, particularly for 1, and that the uptake pattern depends on the ligand. Nuclear microscopic techniques are used for imaging and elemental quantification in whole PC3 cells incubated with 1. Once complexes are added to cell culture media, they decompose, and with time most VIV oxidizes to VV-species. Modeling of speciation when [VIVO(OSO3)(phen)2] (1) is added to cell media is presented. At lower concentrations of 1, VIVO- and phen-containing species are mainly bound to bovine serum albumin, while at higher concentrations [VIVO(phen)n]2+-complexes become relevant, being predicted that the species taken up and mechanisms of action operating depend on the total concentration of complex. This study emphasizes that for these VIVO-systems, and probably for many others involving oxidovanadium or other labile metal complexes, it is not possible to identify active species or propose mechanisms of cytotoxic action without evaluating speciation occurring in cell media.

Vanadium Compounds as Biocatalyst Models.

Peroxidovanadium(V) and oxidovanadium(IV) compounds have been tested as peroxidase-similar compounds. Their catalytic performance was tested on phenol red and pyrogallol substrates. Bromination kinetic studies revealed Michaelis-Menten behavior with respect to phenol red for both complexes. Catalytic efficiency is ~ 104 M-1 min-1. Both vanadium complexes showed the capacity to oxidize pyrogallol, but only the oxidovanadium (IV) complex follows Michaelis-Menten kinetics with respect to this substrate (Km = 1.05 × 10-3 M). Peroxidovanadium(V) complex displayed a more complex mechanism, and further studies became necessary to elucidate it. The structure-activity relationship was also assessed.

Isoprene Polymerization: Catalytic Performance of Iminopyridine Vanadium(III) Chloride versus Vanadium(III) Chloride.

A series of vanadium complexes bearing iminopyridine bidentate ligands with various electronic and steric properties: V1 [CH2Ph], V2 [CMe2CH2CMe3], V3 [Ph] and V4 [2,6-iPr2Ph] were prepared and characterized by IR spectroscopy and microanalytical analysis. The catalytic capacity of all the complexes has been investigated for isoprene polymerization and was controlled by tuning the ligand structure with different N-alkyl and N-aryl groups. Activated by methylaluminoxane (MAO), the aryl-substituted complex V3 [Ph] exhibited high cis-1,4 selectivity (75%), and the resultant polymers had high molecular weights (Mn = 6.6 × 104) and narrow molecular weight distributions (PDI = 2.3). This catalyst showed high activity up to 734.4 kg polymer (mol V)-1 h-1 with excellent thermostability even stable at 70 °C. Compared to the traditional VCl3/MAO catalytic system, iminopyridine-supported V(III) catalysts displayed higher catalytic activities and changed the selectivity of monomer enchainment from trans-1,4 to cis-1,4.

Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process.

The pancreatic cancer is the fourth leading cause of cancer-related death and characterized by one of the lowest five-year survival rate. The current therapeutic options are demonstrating minimal effectiveness, therefore studies on new potential anticancer compounds, with non-significant side effects are highly desirable. Recently, it was demonstrated that vanadium compounds, in particular organic derivatives, exhibit anticancer properties against different type of tumor as well as favorable biodistribution from a pancreatic cancer treatment perspective. In this research, we showed selective cytotoxic effect of vanadium complexes, containing phenanthroline and quinoline as an organic ligands, against human pancreatic ductal adenocarcinoma cell line (PANC-1), compared to non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE). Results exhibited that vanadium complexes inhibited autophagy process in selective cytotoxic concentration as well as caused the cell cycle arrest in G2/M phase associated with mitotic catastrophe and increased level of reactive oxygen species (ROS). Moreover, in higher concentration, vanadium derivatives induced a mix type of cell death in PANC-1 cells, including apoptotic and necroptotic process. Our investigation emphasizes the anticancer potential of vanadium complexes by indicating their selective cytotoxic activity, through different process posed by alternative type of cell deaths to apoptosis-resistant cancer cells. Further studies supporting the therapeutic potential of vanadium in pancreatic cancer treatment is highly recommended.