Current Medicinal Chemistry - Volume 28, Issue 35, 2021

Background: Essential metal ions play a specific and fundamental role in human metabolism. Their homeostasis is finely tuned, and any concentration imbalance in the form of deficiency or excess could lead to a progressive reduction and failure of normal biological function, to severe physiological and clinical outcomes, may eventually causing death. Conversely, non-essential metals are not necessary for life, and only noxious effects could arise after their exposure. Large environmental amounts of such chemicals come from both natural and anthropogenic sources, with the latter being predominant because of human activities. The dissipation of toxic metals contaminates water, air, soil, and food, causing a series of chronic and acute syndromes. Objective: This review discusses the toxicity of non-essential metals considering their peculiar chemical characteristics, such as different forms, hard-soft character, oxidation states, binding capabilities, and solubility, which can influence their speciation in biological systems, and subsequently, the main cellular targets. Particular focus is given to selected toxic metals, major non-essential metals, or semimetals related to toxicity, such as mercury, lead, cadmium, chromium, nickel, and arsenic. In addition, we provide indications on the possible treatments/interventions for metal poisoning based on chelation therapy. Conclusion: Toxic metal ions can exert their peculiar harmful effects in several ways. They strongly coordinate with important biological molecules on the basis of their chemical- physical characteristics (mainly HSAB properties) or replace essential metal ions from their natural locations in proteins, enzymes, or hard structures, such as bones or teeth. Metals with redox properties could be key inducers of reactive oxygen species, leading to oxidative stress and cellular damage. Therapeutic detoxification, through complexation of toxic metal ions by specific chelating agents, appears an efficacious clinical strategy, mainly in acute cases of metal intoxication.

There has been a long tradition for a broad spectrum of applications of both natural and synthetic hydroxamic acids and derivatives. Even nowadays, a huge number of newly designed representatives (from different monohydroxamate-based compounds to siderophore conjugates) are used to develop potential drug candidates with desired activities. Since these compounds are effective metal-chelating agents, their biological roles and actions as well as their various applications, e.g., in the medicinal practice, are all in direct correlation with their metal complexation. Consequently, the knowledge of the stoichiometry and binding modes of metal complexes with hydroxamic acid-based ligands, their thermodynamic parameters, and speciation profiles in solution are crucial for scientists working in any of the above-mentioned fields. This review, in addition to presenting a few factors, which might affect the metal-binding capabilities of these organic ligands, displays and summarizes the different parameters typically used to give the stoichiometry, composition, and stability of the species formed in a solution equilibrium system in measurable concentration. Discussion of the possibilities for quantitative comparison of metal-binding effectivity and selectivity of various hydroxamic acids with each other by using solution equilibrium data is also the focus of this publication.

Although most of the harmful radionuclides are of anthropogenic origin and released from military or industrial processes, radioactive substances, such as uranium, also occur naturally in the environment. Low standards of care at nuclear facilities can lead to the contamination of employees with radionuclides due to inhalation of gases or dust or contamination of skin or wounds. Various sources for radionuclide exposure may present concerns for radioactive polonium or plutonium exposure, for instance, terrorist actions on the infrastructure, such as on drinking water basins. Early health effects after extensive radiation exposure may be vomiting, headaches, and fatigue, followed by bone marrow depression, fever, and diarrhea. The main purpose of radionuclide mobilization is to minimize the radiation dose. Since some of the important radionuclides, such as polonium and plutonium, have very long biological half-times after their deposition in bone, liver or kidneys, rapid initiation of chelation treatment is usually imperative after a contamination event. The antidote DMPS (dimercapto-propanesulfonate) is considered the drug of choice for polonium decorporation. DTPA (diethylenetriamine pentaacetate) is a potent chelator especially approved for radionuclide mobilization, including polonium and other actinides. Other chelators and drugs are under investigation as potential chelators of transuranic elements.

Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative disorder worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Currently available drugs are used, mainly to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g., Cu, Fe, Zn) and of protein misfolding (β-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.

Polyphenols are a class of compounds, produced by plants, which share the ability to act as potent antioxidants. First investigations on polyphenols’ antioxidant activity are dated almost twenty years ago when their relationship and implication with the prevention and treatment of cancer was proposed for the first time. Later, in the early 2000s, the neuroprotective effects of several polyphenols were demonstrated. Nowadays, the benefits of a plethora of polyphenols have been studied and their ameliorating effects in several disease conditions, like cancer, cardiac and neuronal diseases are widely recognised. More than 1000 papers dealing with polyphenols and Alzheimer’s disease have been published so far, describing the antioxidant properties, the metal chelating features and the anti-aggregating behavior of these compounds. The aim of this review is to rationalize, from a chemical point of view, the metal complexation mechanisms of polyphenols related to two significant events of Alzheimer’s disease: oxidative stress and metal ion dyshomeostasis. In order to address this issue, we have herein discussed several aspects implicated in Alzheimer’s disease and polyphenols involved in the treatment of the disease.

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.

Some transition metals, like manganese, iron, cobalt, nickel, copper and zinc, required for the biosynthesis of metalloenzymes and metalloproteins, are essential micronutrients for the growth and development of pathogenic microorganisms. Among the defenses put in place by the host organism, the so-called “nutritional immunity” consists of reducing the availability of micronutrients and thus “starving” the pathogen. In the case of metals, microorganisms can fight the nutritional immunity in different ways, i.e. by directly recruiting the metal ion or capturing an extracellular metalloprotein or also through the synthesis of specific metallophores which allow importing the metal in the form of a chelate complex. The best known and most studied metallophores are those directed to iron (siderophores), but analogous chelators are also expressed by microorganisms to capture other metals, such as zinc. An efficient zinc recruitment can also be achieved by means of specialized zinc-binding proteins. A deep knowledge of the properties, structure and action mechanisms of extracytoplasmic zinc chelators can be a powerful tool to find out new therapeutic strategies against the antibiotic and/or antifungal resistance. This review aims to collect the knowledge concerning zincophores (small molecules and proteins in charge of zinc acquisition) expressed by bacterial or fungal microorganisms that are pathogenic for the human body.

Biospeciation of some of the most studied vanadium (symbol V) complexes with biological or medicinal activity is discussed in this review in order to emphasize the importance of the distribution of V species in biological media. The exact knowledge of the chemical species present in blood or cells may provide essential information regarding the biological effect of V potential drugs. In blood serum, vanadium species can interact with low (citrate, lactate, oxalate, amino acids, etc., indicated with bL) and high molecular mass (proteins like transferrin, albumin, immunoglobulins, etc.) components, while the interaction with red blood cells can interfere with the transport of these drugs towards the target cells. The interaction of bLs and proteins is discussed through the analysis of instrumental and computational data. The fate of the active V species, when these are in the real serum samples and when they reach and cross cell membranes, is also discussed. The differences in the V complexes selected in this review (donor atoms, stability, coordination geometry, electric charge, hydrolipophilicity balance, substituents and redox properties) cover all the possible modes of interaction with bLs and proteins, allowing for the biodistribution of the studied compounds to be predicted. This approach could be applied to newly synthesized potential V drugs.