Multipurpose Iron-Chelating Ligands Inspired by Bioavailable Molecules.

Because of their capacity to bind metals, metal chelators are primarily employed for therapeutic purposes, but they can also find applications as colorimetric reagents and cleaning solutions as well as in soil remediation, electroplating, waste treatment, and so on. For instance, iron-chelation therapy, which is used to treat iron-overload disorders, involves removing excess iron from the blood through the use of particular molecules, like deferoxamine, that have the ability to chelate the metal. The creation of bioinspired and biodegradable chelating agents is a crucial objective that draws inspiration from natural products. In this context, starting from bioavailable molecules such as maltol and pyrogallol, new molecules have been synthetized and characterized by potentiometry, infrared spectroscopy and cyclic voltammetry. Finally, the ability of these to bind iron has been investigated, and the stability constants of ferric complexes are measured using spectrophotometry. These compounds offer intriguing scaffolds for an innovative class of versatile, multipurpose chelating agents.

A family of kojic acid derivatives aimed to remediation of Pb2+ and Cd2.

The present work analyzes the complex formation ability towards Pb2+ and Cd2+ of a series of kojic acid derivatives that join the chelating properties of the pyrone molecules and those of polyamines, with the aim of evaluating how the different effects of oxygen and nitrogen coordinating groups act on the stability of metal complexes. Experimental research is carried out using potentiometric and spectrophotometric techniques supported by 1H and 13C NMR spectroscopy and DFT calculations. Actually, a different coordination mechanism toward Pb2+ and Cd2+ was proved: in the case of Pb2+, coordination takes place exclusively via the oxygen atoms, while the contribute of the nitrogen atoms appears relevant in the case of Cd2+. Lead complexes of all the studied ligands are characterized by significantly stronger stability than those of cadmium. Finally, on the basis of the measured complex formation stabilities, some of the proposed molecules seems promising effective ligands for lead and cadmium ion decorporation from polluted soils or waste waters.

A Multi-Technique Investigation of the Complex Formation Equilibria between Bis-Deferiprone Derivatives and Oxidovanadium (IV).

The increasing biomedical interest in high-stability oxidovanadium(IV) complexes with hydroxypyridinone ligands leads us to investigate the complex formation equilibria of VIVO2+ ion with a tetradentate ligand, named KC21, which contains two 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (deferiprone) moieties, and with the simple bidentate ligand that constitutes the basic unit of KC21, for comparison, named L5. These equilibrium studies were conducted with joined potentiometric-spectrophotometric titrations, and the results were substantiated with EPR measurements at variable pH values. This multi-technique study gave evidence of the formation of an extremely stable 1:1 complex between KC21 and oxidovanadium(IV) at a physiological pH, which could find promising pharmacological applications.

Thermodynamic Study of Oxidovanadium(IV) with Kojic Acid Derivatives: A Multi-Technique Approach.

The good chelating properties of hydroxypyrone (HPO) derivatives towards oxidovanadium(IV) cation, VIVO2+, constitute the precondition for the development of new insulin-mimetic and anticancer compounds. In the present work, we examined the VIVO2+ complex formation equilibria of two kojic acid (KA) derivatives, L4 and L9, structurally constituted by two kojic acid units linked in position 6 through methylene diamine and diethyl-ethylenediamine, respectively. These chemical systems have been characterized in solution by the combined use of various complementary techniques, as UV-vis spectrophotometry, potentiometry, NMR and EPR spectroscopy, ESI-MS spectrometry, and DFT calculations. The thermodynamic approach allowed proposing a chemical coordination model and the calculation of the complex formation constants. Both ligands L4 and L9 form 1:1 binuclear complexes at acidic and physiological pHs, with various protonation degrees in which two KA units coordinate each VIVO2+ ion. The joined use of different techniques allowed reaching a coherent vision of the complexation models of the two ligands toward oxidovanadium(IV) ion in aqueous solution. The high stability of the formed species and the binuclear structure may favor their biological action, and represent a good starting point toward the design of new pharmacologically active vanadium species.

The Aging Kidney-As Influenced by Heavy Metal Exposure and Selenium Supplementation.

The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50-60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance.

The Potential Clinical Properties of Magnesium.

A significant percentage of costs in pharmaceutical markets is devoted to supplements due to the confidence of consumers in the beneficial effects of these products. Magnesium is one of the supplements with enduring and increasing popularity. According to what is reported online, this metal ion can cure or prevent almost all kinds of diseases. This review aims at illustrating a series of scientifically demonstrated cases in which magnesium was used in clinical practice. Except for its ordinary use as antacid and laxative, other ascertained uses, reported in scientific literature, consist of helping to treat several diseases such as nocturnal leg cramps, pre-eclampsia, diabetes, depression, Parkinson's and Alzheimer's disease, hypertension, some types of arrhythmias, asthma, migraine headaches, epilepsy, cerebral haemorrhage, and stroke. However, many of these promising uses of magnesium require further studies to define the involved molecular mechanisms which should help establishing its uses in relation to the prolonged use of supplements.

Chelating Agents in Soil Remediation: A New Method for a Pragmatic Choice of the Right Chelator.

Soil pollution by metal ions constitutes one of the most significant environmental problems in the world, being the ecosystems of extended areas wholly compromised. The remediation of soils is an impelling necessity, and different methodologies are used and studied for reaching this goal. Among them, the application of chelating agents is one of the most promising since it could allow the removal of metal ions while preserving the most meaningful properties of the original soils. The research in this field requires the joined contribute of different expertise spanning from biology to chemistry. In this work, we propose a parsimonious and pragmatic approach for screening among a range of potential chelating agents. This methodology, the Nurchi's method, is based on an extension of the Reilley procedure for EDTA titrations. This allows forecasting the binding ability of chelating agents toward the target polluting metal ions and those typically found in soils, based on the knowledge of the related protonation and complex formation constants. The method is thoroughly developed, and then tested by application to some representative cases. Its use and relevance in biomedical and industrial applications is also discussed.

An aggregation-induced emission active vitamin B6 cofactor derivative: application in pH sensing and detection of latent fingerprints.

Aggregation-induced emission (AIE) properties of an easy-to-prepare and structurally planar Schiff base derivative of the vitamin B6 cofactor pyridoxal (L) were investigated in DMSO-H2O mixed solvents. Compound L showed weak fluorescence (λem = 425 nm) in pure DMSO, but increasing the fraction of water in DMSO resulted in a significant fluorescence enhancement at 575 nm due to the restriction of intramolecular rotation (RIR) of L upon aggregation. SEM analyses revealed the formation of hairy micelle-like or needle-shaped self-assemblies/aggregates of L. The DFT calculations were performed to examine the tendency of L to form self-aggregates, and the results indicate the formation of several intramolecular non-covalent interactions that energetically favored the self-aggregation of L. The pH sensing study revealed that the red-emission of aggregates of L between pH 5.9 and 9.0 turned into green emission at the basic pH with the estimated pKa values of 9.39 and 10.22. Further, the aggregates of L were applied for the visualization of latent fingerprints (LFPs) over a non-porous glass slide.

Gold Nanoparticles: A New Golden Era in Oncology?

In recent years, the spectrum of possible applications of gold in diagnostics and therapeutic approaches in clinical practice has changed significantly, becoming surprisingly broad. Nowadays, gold-based therapeutic agents are used in the therapy of multiple human diseases, ranging from degenerative to infectious diseases and, in particular, to cancer. At the basis of these performances of gold, there is the development of new gold-based nanoparticles, characterized by a promising risk/benefit ratio that favors their introduction in clinical trials. Gold nanoparticles appear as attractive elements in nanomedicine, a branch of modern clinical medicine, which combines high selectivity in targeting tumor cells and low toxicity. Thanks to these peculiar characteristics, gold nanoparticles appear as the starting point for the development of new gold-based therapeutic strategies in oncology. Here, the new gold-based therapeutic agents developed in recent years are described, with particular emphasis on the possible applications in clinical practice as anticancer agents, with the aim that their application will give rise to a new golden age in oncology and a breakthrough in the fight against cancer.

Arsenic Toxicity: Molecular Targets and Therapeutic Agents.

: High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.

New strong extrafunctionalizable tris(3,4-HP) and bis(3,4-HP) metal sequestering agents: synthesis, solution and in vivo metal chelation.

Finding new multifunctional metal binders to be potentially used in diagnosis or therapy has been a subject of major challenge. Hydroxypyridinones have long been recognized as privileged chelating structures for the design of metal chelating drugs, especially towards hard metal ions, in view of their decorporation in metal overload disorders. Thus, pursuing our strategy of engineering new polydentate 3-hydroxy-4-pyridinones (3,4-HP) with extrafunctionalization capacity for sensing or targeting purposes, we report herein the synthesis and full characterization of a hexadentate (tris-3,4-HP) and a tetradentate (bis-3,4-HP) ligand, possessing three and two 3,4-HP arms N-attached to an aminomethanetrispropionic acid backbone, respectively. Thus, as compared with previously reported analogues, each ligand possesses an extra free amino group ready for further functionalization. Their chelating capacity towards Fe and Al was evaluated in aqueous solution, by potentiometric and spectroscopic techniques, and they proved to be strong sequestering agents for these metal ions without depletion of Zn, an essential biometal. Their excellent in vivo metal-decorporation capacity was also evidenced in mice injected with a radiotracer (67Ga) as an animal model of metal overload pathological situations. These findings provide encouragement for further ongoing extrafunctionalizations in view of several potential biomedical applications.

A Review on Coordination Properties of Thiol-Containing Chelating Agents Towards Mercury, Cadmium, and Lead.

The present article reviews the clinical use of thiol-based metal chelators in intoxications and overexposure with mercury (Hg), cadmium (Cd), and lead (Pb). Currently, very few commercially available pharmaceuticals can successfully reduce or prevent the toxicity of these metals. The metal chelator meso-2,3-dimercaptosuccinic acid (DMSA) is considerably less toxic than the classical agent British anti-Lewisite (BAL, 2,3-dimercaptopropanol) and is the recommended agent in poisonings with Pb and organic Hg. Its toxicity is also lower than that of DMPS (dimercaptopropane sulfonate), although DMPS is the recommended agent in acute poisonings with Hg salts. It is suggested that intracellular Cd deposits and cerebral deposits of inorganic Hg, to some extent, can be mobilized by a combination of antidotes, but clinical experience with such combinations are lacking. Alpha-lipoic acid (α-LA) has been suggested for toxic metal detoxification but is not considered a drug of choice in clinical practice. The molecular mechanisms and chemical equilibria of complex formation of the chelators with the metal ions Hg2+, Cd2+, and Pb2+ are reviewed since insight into these reactions can provide a basis for further development of therapeutics.

Recent Advances on Iron(III) Selective Fluorescent Probes with Possible Applications in Bioimaging.

Iron(III) is well-known to play a vital role in a variety of metabolic processes in almost all living systems, including the human body. However, the excess or deficiency of Fe3+ from the normal permissible limit can cause serious health problems. Therefore, novel analytical methods are developed for the simple, direct, and cost-effective monitoring of Fe3+ concentration in various environmental and biological samples. Because of the high selectivity and sensitivity, fast response time, and simplicity, the fluorescent-based molecular probes have been developed extensively in the past few decades to detect Fe3+. This review was narrated to summarize the Fe3+-selective fluorescent probes that show fluorescence enhancement (turn-on) and ratiometric response. The Fe3+ sensing ability, mechanisms along with the analytical novelties of recently reported 77 fluorescent probes are discussed.

Insights on alpha lipoic and dihydrolipoic acids as promising scavengers of oxidative stress and possible chelators in mercury toxicology.

Alpha lipoic acid (α-LA) and its reduced form dihydrolipoic acid (DHLA) have been historically considered as excellent anti-oxidants and oxidative stress scavengers. Upon oxidation with reactive oxygen species (ROS) and pro-oxidants, α-LA may be reconstituted from DHLA and other reduced forms. Oxidative stress is one of the fundamental causes of functional degeneration, autophagy and apoptosis leading to cytotoxicity and loss of cell survival, often due to exposure to xenobiotics, pollutants, heavy metals, and other environmental and endogenous toxicants. α-LA and DHLA can react with these molecules to strengthen the primary antioxidant defense system during cell injury. The compound α-LA is suggested for heavy metal detoxification, in particular for supporting the mercury (Hg) detoxifying process. Mercury is one of the major environmental toxicant, particularly noxious even upon limited exposure. Oxidative stress pathways have been identified as a key upstream event for Hg-induced toxicity in humans and animals. However, very few existing drugs to date can successfully prevent or reduce Hg toxicity. Although several thiol-based chelators, such as British Anti-Lewisite (2,3-dimercaptopropanol, BAL), meso-2,3-dimercaptosuccinic acid (DMSA), and sodium 2,3-dimercapto-1-propanesulfonate (DMPS), have shown promise for ameliorating Hg intoxication. In this review, the potential role of α-LA and DHLA in scavenging toxic metals and other xenobiotics is discussed, focusing especially on the mechanisms of actions of α-LA and DHLA as potential antioxidants towards Hg-induced toxicity.

The essential metals for humans: a brief overview.

The human body needs about 20 essential elements in order to function properly and among them, for certain, 10 are metal elements, though for every metal we do need, there is another one in our body we could do without it. Until about 1950 poor attention was given to the so-called "inorganic elements" and while researches on "organic elements" (C, N, O and H) and organic compounds were given high priority, studies on essential inorganic elements were left aside. Base on current knowledge it is ascertained today that metals such as Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn and Mo are essential elements for life and our body must have appropriate amounts of them. Here a brief overview to highlight their importance and current knowledge about their essentiality.

Iron Chelation for Iron Overload in Thalassemia.

This chapter is devoted to the chelation treatment of transfusion-dependent thalassemia patients. After a brief overview on the pathophysiology of iron overload and on the methods to quantify it in different organs, the chelation therapy is discussed, giving particular attention to the chemical and biomedical requisites. The main tasks of an iron chelator should be the scavenging of excess iron, allowing an equilibrium between iron supplied by transfusions and that removed with chelation, and protection of the individual from the poisonous effects of circulating iron. The chelating agents in clinical use are presented, illustrating the main chemical and pharmacological features, together with a comparative cost analysis of their treatments. As a final section, an overview is provided on chelators undergoing clinical trials, and on research in progress.

Complex formation equilibria of polyamine ligands with copper(II) and zinc(II).

A comprehensive study of the protonation equilibria of a series of polyamine ligands along with their complex formation equilibria with Cu2+ and Zn2+ is reported in this work. The primary aim of this study has been the achievement of homogeneous thermodynamic data on these ligands, in order to evaluate their influence on the homeostatic equilibria of essential metal ions (Cu2+ and Zn2+) in biological fluids. These polyamines are largely used as linkers in the building of chelating agents for iron overload. Potentiometric and spectrophotometric techniques were used for the characterization of protonation and complex formation constants. In addition, the characterization of the formed complexes is discussed together with selected solid-state crystal structures, remarking the influence of the length of the chain and of the linear or tetradentate tripod nature of the polyamine ligands on the stability of the complexes.

A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe3+, Al3+, Cu2+ and Zn2+, and in vivo bioassays.

This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe3+, Al3+, Cu2+ and Zn2+ ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium. The stability of the formed complexes with Fe3+ and Al3+ are high enough to consider the new ligand for further studies for its clinical applications as a chelating agent. Biodistribution studies were carried out to assess the capacity the ligand for mobilization of gallium in 67Ga-citrate injected mice. These studies demonstrated that this ligand efficiently chelates the radiometal in our animal model, which suggests that it can be a promising candidate as sequestering agent of iron and other hard trivalent metal ions. Furthermore, the good zinc complexation capacity appears as a stimulating result taking into a potential use of this new ligand in analytical chemistry as well as in agricultural and environmental applications.

Equilibrium studies of new bis-hydroxypyrone derivatives with Fe3+, Al3+, Cu2+ and Zn2.

This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe3+, Al3+, Cu2+ and Zn2+. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2. The different anchoring position of the linker, as well as the linker length, can affect both protonation and complex formation equilibria. A thorough study of the protonation and complex formation equilibria of the three ligands toward the metal ions is presented based on combined potentiometric and spectroscopic studies, and 1H NMR. The obtained results allow remarking that the orientation of the oxygen atoms in the kojic acid units, related to the anchoring position of the linker, strongly affects the protonation constants, while the chelating ability is practically unaffected. The trivalent metal ions form stable complexes with a 2:3 metal to ligand stoichiometry through the oxygen donor atoms of the ligands, whereas divalent metal ions form binuclear complexes for which the nitrogen atoms from the linker might be involved in the coordination sphere. The stability of the complexes decreases with linker length, and the selectivity of the ligands toward metal ions grows in the order Zn2+ < Cu2+ < Al3+ < Fe3+.