Multifunctional 8‐Hydroxyquinoline‐Appended Cyclodextrins as New Inhibitors of Metal‐Induced Protein Aggregation

Mounting evidence suggests a pivotal role of metal imbalances in protein misfolding and amyloid diseases. As such, metal ions represent a promising therapeutic target. In this context, the synthesis of chelators that also contain complementary functionalities to combat the multifactorial nature of neurodegenerative diseases is a highly topical issue. We report two new 8‐hydroxyquinoline‐appended cyclodextrins and highlight their multifunctional properties, including their Cu^II and Zn^II binding abilities, and capacity to act as antioxidants and metal‐induced antiaggregants. In particular, the latter property has been applied in the development of an effective assay that exploits the formation of amyloid fibrils when β‐lactoglobulin A is heated in the presence of metal ions.     

Purification of S-oxynitrilase from Sorghum bicolor by immobilized metal ion affinity chromatography on different carrier materials.

The purification of the hydroxynitrile lyase (EC 4.1.2.11, S-oxynitrilase) from Sorghum bicolor is compared using different strategies. A new procedure is presented, which exploits the affinity of S-oxynitrilase towards metal ions as a key step in purification. The metal ions are immobilized by chelators on different carrier materials, e.g. Sepharose beads, microporous membranes or poly(ethylene glycol). A systematic examination demonstrates the excellent potential of immobilized metal affinity chromatography as a preparative separation method.     

Different approaches to the study of chelating agents for iron and aluminium overload pathologies

Our objective is to illustrate the activity of the groups operating in Italy involved in identification and study of new chelating agents, mainly intended for treatment of human pathology correlated with metal overload. The objective of “chelation therapy” is removal of toxic metal ions from the human body or attenuation of their toxicity by transforming them into less toxic compounds or by dislocating them from the site at which they exert a toxic action. Because most of this research activity is related to chelating agents for iron and aluminium, diseases related to these two metal ions are briefly treated. Iron overload is the most common metal toxicity disease worldwide. The toxicity of aluminium in dialysis patients was a serious problem for haemodialysis units in the seventies and eighties of the last century. In particular, this review focuses on research performed by the group at Cagliari and Ferrara, and by that at Padova. The former is studying, above all, bisphosphonate and kojic acid derivatives, and the latter is investigating 3,4-hydroxypyridinecarboxylic acids with differently substituted pyridinic rings.

Human diseases related to aluminium overload

Abstract  

In this paper attention is devoted to the role of aluminium in osteodistrophy and dialysis dementia. In fact, these diseases, in spite of the actions that have drastically reduced their occurrence, have so far constituted a cause of great medical concern. As a preliminary point, some aspects concerning the solution chemistry of aluminium are considered, then the medical problems are described and finally the chelation therapy of aluminium overload, giving some insight on the chelators recently proposed.     

Element speciation analysis by capillary electrophoresis

An overview of recent developments in the application of capillary electrophoresis to simultaneous separation and determination of different chemical forms of an inorganic element is presented, with particular emphasis placed on metal speciation analysis. Examples of species analysis are addressed, covering metal ions in different oxidation states, metal complexes with inorganic and organic ligands, metalloid oxoanions, organometallic compounds, ionic non-metal species, etc. The speciation performance of capillary electrophoresis is illustrated by a number of practically relevant applications. The method's strengths and current limitations with regard to chemical speciation studies are critically discussed.     

Cyclodextrins 3‐Functionalized with 8‐Hydroxyquinolines: Copper‐Binding Ability and Inhibition of Synuclein Aggregation

Neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are multifactorial disorders related to protein aggregation, metal dyshomeostasis, and oxidative stress. To advance understanding in this area and to contribute to therapeutic development, many efforts have been directed at devising suitable agents that can target metal ions associated with relevant biomolecules such as α‐synuclein. This paper presents a new cyclodextrin–8‐hydroxyquinoline conjugate and discusses the properties of four cyclodextrins 3‐functionalized with 8‐hydroxyquinoline as copper(II) chelators and inhibitors of copper‐induced synuclein aggregation. The encouraging results establish the potential of cyclodextrin–8‐hydroxyquinoline conjugates as chelators for the control of copper toxicity.     

Copper-related diseases: From chemistry to molecular pathology

The aim of this review is to give a general view on the current status of the scientific basis for the role of copper in human health and disease, outlining the roles of copper in human metabolism and bioenergetics, its coordination chemistry as well as its biological ligands involved in the multiple steps of metal assimilation and distribution. Copper bioavailability depends on four main factors: (1) the absorption of copper from the gastrointestinal tract; (2) copper transport in the portal blood; (3) the extraction of copper by hepatocytes from the portal blood supply; (4) copper uptake by peripheral tissues and by the central nervous system. The most important copper pumps, providing a permeation pathway for copper ions in man, such as hCTR1, hCTR2, DMT1, ATP7A, ATP7B, and MURR1, are extensively discussed. Different theories on the putative role of ceruloplasmin in copper transport in blood are presented. Data on interactions among other trace elements and copper, from the level of enterocyte to other systems in the body, are also shown. Finally, the function of different drugs, chelators and non-chelating agents, utilized in clinical practice in the therapy of Wilson's disease is treated, in particular the “reductive chelation” of penicillamine is discussed.     

神经生物系统中的配位化学问题*

从上个世纪末开始,金属离子在神经生物系统中的作用受到了广泛的关注。生物学家开始注意到一些重要生理过程中金属离子的化学及生物化学问题。本文总结了近年来在该领域的最新研究进展,并着重介绍了过渡金属离子与神经退行性疾病之间的联系。     

Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

Upon bacterial infection, one of the defense mechanisms of the host is the withdrawal of essential metal ions, in particular iron, which leads to “nutritional immunity”. However, bacteria have evolved strategies to overcome iron starvation, for example, by stealing iron from the host or other bacteria through specific iron chelators with high binding affinity. Fortunately, these complex interactions between the host and pathogen that lead to metal homeostasis provide several opportunities for interception and, thus, allow the development of novel antibacterial compounds. This Review focuses on iron, discusses recent highlights, and gives some future perspectives which are relevant in the fight against antibiotic resistance.     

Aluminium speciation in relation to aluminium bioavailability, metabolism and toxicity

Aluminium toxicity may act in two distinct ways, depending on the level of contamination. Relatively low aluminium levels from environmental origin (mainly from drinking water poor in silica) have been shown to be statistically associated with senile dementias of Alzheimer type (chronic intoxication). In addition, high aluminium therapeutic levels (from phosphate binders, antacids, …) can induce different, more rapid, symptoms (acute intoxication). In all cases, aluminium toxicity is largely conditioned by aluminium bioavailability, which in turn hinges upon aluminium coordination chemistry in vivo. The highly polarising power of the Al³⁺ ion dictates its particular affinity for oxygen donors that abound in essential biomolecules and dietary substances. The influence of these substances on aluminium bioavailability, metabolism and toxicity can be assessed through animal models. However, understanding the mechanisms through which aluminium-ligand interactions may influence physiological processes on the molecular level requires a knowledge of the speciation of the metal in the main biofluids. Access to this critical information can a priori be gained through direct experimental analysis of relevant biological samples. It is in this way that aluminium protein-bound fractions, involving essentially transferrin, have been identified, but using such a direct approach to analyse the ultrafiltrable pool of the metal is a virtually insurmountable task, hence the necessity to have recourse to computer-aided speciation techniques based on simulation models. Following a previous review published in this journal on nearly the same topic [Coord. Chem. Rev. 149 (1996) 241], this article updates the knowledge available on both biological and chemical fronts. After a review of experimental investigations led on the roles of aluminium-ligand interactions in aluminium bioavailability, metabolism and toxicity, contributions of experimental and computer-aided speciation to the understanding of the relevant processes are then analysed. Significant progress has been made in the diverse aspects of the biological field, in particular, in relation to the role of dietary ligands on aluminium gastrointestinal absorption, excretion and tissue distribution. Also, very intensive research has been pursued on the design of new aluminium sequestering agents to treat acute intoxications. Some progress has also been made on the chemical side relative to computer-aided speciation applications to gastrointestinal and blood plasma conditions. However, the gap is increasing between the large body of observations made by physiologists and toxicologists and the few data painfully obtained by coordination chemists to interpret the relevant phenomena.     

The polarographic determination of aluminium : The elimination of interfering elements and the determination ofaluminium by oscillographic polarography

A study is reported of the effect of some ion species on the determination of aluminium by osicillographic polarography under the conditions. previously established. The development of an electrolytic procedure for the removal of interfering metal ions is described and details of unsuccessful attempts to remove interference by fluoride are given. The method for the determination of aluminium is given in detail and result obtained with it are presented.     

Separation and analysis of aluminium(III) by cation exchange ion chromatography

A method for the determination of aluminium(III) ions based on separation by cation exchange column chromatography and detection by conductivity detector has been developed. It is fast and reliable, and can be used for the separation and analysis of aluminium(III) ions from other metal ions like Mg(II), Mn(II), Zn(II), Co(II), Ca(II), Sr(II), rare earth elements like Lu(III), Tm(III), and Gd(III), which are eluted at different times and so do not interfere. Effect of p-phenylene diamine concentration present in the eluent, presence of other metal ions and effect of various anions present in the injection sample on the separation and analysis of aluminium(III) ions have also been studied.     

Unusual binding ability of vancomycin towards Cu2+ ions

Vancomycin, a "last chance" antibiotic, is a glycopeptide consisting of an oligopeptide unit being potentially the effective binder of Cu2+ ions. The potentiometric and spectroscopic studies (UV-Vis, CD, EPR, NMR) have shown that, indeed, the peptide unit binds cupric ions very effectively forming almost instantly the 3N complex involving the N-terminal nitrogen donors in the metal ion coordination. The comparison of the binding ability of vancomycin with other peptide chelators clearly shows the efficiency of this antibiotic in metal ion coordination. It is very likely that Cu2+ ions may play a crucial role in the pharmacology of vancomycin, particularly when administered in high doses.     

Manipulating Metal‐to‐Metal Charge Transfer for Materials with Switchable Functionality

Metal‐to‐metal charge transfer (MMCT) describes electron transfer between metal ions, to generate valence isomers with markedly different electronic configurations. In particular, MMCT changes the spin states of single‐metal sites and the coupling interactions between them, while also changing the symmetry in charge distribution. The result is a drastic change in both magnetic and electric properties of the affected material. Moreover, MMCT causes significant variation in bond length and absorption spectra, and induces unusual thermal expansion and photochromic behavior. Thus, materials demonstrating MMCT in response to external stimuli are excellent candidates for switchable multifunctional devices with synergistic responses. In this Minireview, recent progress in utilizing MMCT units as actuators to tune magnetic, electric, thermal expansion, and photochromic properties in cyanide‐bridged systems is highlighted, and emphasis is given to the remaining challenges and future perspectives in the field.     

Copper(I) and copper(II) inhibit Aβ peptides proteolysis by insulin-degrading enzyme differently: implications for metallostasis alteration in Alzheimer's disease

Accumulation of neurotoxic amyloid-β peptide (Aβ) and alteration of metal homeostasis (metallostasis) in the brain are two main factors that have been very often associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Aβ is constantly produced from the amyloidprecursor-protein APP precursor and immediately catabolized under normal conditions, whereas dysmetabolism of Aβ and/or metal ions seems to lead to a pathological deposition. Although insulin-degrading enzyme (IDE) is the main metalloprotease involved in Aβ degradation in the brain being up-regulated in some areas of AD brains, the role of IDE for the onset and development of AD is far from being understood. Moreover, the biomolecular mechanisms involved in the recognition and interaction between IDE and its substrates are still obscure. In spite of the important role of metals (such as copper, aluminum, and zinc), which has brought us to propose a "metal hypothesis of AD", a targeted study of the effect of metallostasis on IDE activity has never been carried out. In this work, we have investigated the role that various metal ions (i.e., Cu(2+), Cu(+), Zn(2+), Ag(+), and Al(3+)) play in modulating the interaction between IDE and two Aβ peptide fragments, namely Aβ(1-16) and Aβ(16-28). It was therefore possible to identify the direct effect that such metal ions have on IDE structure and enzymatic activity without interferences caused by metal-induced substrate modifications. Mass spectrometry and kinetic studies revealed that, among all the metal ions tested, only Cu(2+), Cu(+), and Ag(+) have an inhibitory effect on IDE activity. Moreover, the inhibition of copper(II) is reversed by adding zinc(II), whereas the monovalent cations affect the enzyme activity irreversibly. The molecular basis of their action on the enzyme is also discussed on the basis of computational investigations.     

Recent Developments in Lanthanide Single‐Molecule Magnets

Single‐molecule magnets (SMMs) exhibiting slow relaxation of magnetization of purely molecular origin are highly attractive owing to their potential applications in spintronic devices, high‐density information storage, and quantum computing. In particular, lanthanide SMMs have been playing a major role in the advancement of this field because of the large intrinsic magnetic anisotropy of lanthanide metal ions. Herein, some recent breakthroughs that are changing the perspective of the field are highlighted, with special emphasis on synthetic strategies towards the design of high‐performance SMMs.     

Nuclear magnetic resonance studies of edta in the presence of excess calcium or strontium

The equilibria which exist between metal ions, ethylenediaminetetraacetic acid (EDTA), and the resulting chelates have been thoroughly investigated by many techniques, emphasis being placed on the study of complexes containing a 1:1 ratio of metal ion to ligand. The results presented here are concerned with the observation of the chemical shift of the nonlabile protons of EDTA when excess calcium or strontium ions are present. The results yield evidence for a 2:1 complex. Formation constants for the equilibria believed to be in effect are given and a possible structure of the 2:1 complex is discussed.     

Simultaneous spectrofluorimetric determination of iron and manganese by a differential kinetic catalytic method

A kinetic method is presented for the simultaneous determination of iron(III) and manganese(II) based on the different reaction rates resulting from the catalytic effect of both metal ions on the oxidation of 2-hydroxybenzaldehyde thiosemicarbazone by hydrogen peroxide in an ammoniacal medium. The reaction is monitored spectrofluorimetrically at 440 nm and with excitation at 365 nm. Two sets of reaction conditions are established to maximize the effect of manganese compared to iron, and vice versa, and the data are evaluated from simultaneous equations. Mixtures of these metal ions at ng ml^?1 levels for iron/manganese ratios from 8:1 to 1:2 can be determined with an accuracy and precition of about 3% and 1%, respectively. The methods has been applied successfully to the determination of both metals in aluminium and copper alloys, beer, cheeses and soils.     

In silico strategies for the selection of chelating compounds with potential application in metal-promoted neurodegenerative diseases

The development of new strategies to find commercial molecules with promising biochemical features is a main target in the field of biomedicine chemistry. In this work we present an in silico-based protocol that allows identifying commercial compounds with suitable metal coordinating and pharmacokinetic properties to act as metal-ion chelators in metal-promoted neurodegenerative diseases (MpND). Selection of the chelating ligands is done by combining quantum chemical calculations with the search of commercial compounds on different databases via virtual screening. Starting from different designed molecular frameworks, which mainly constitute the binding site, the virtual screening on databases facilitates the identification of different commercial molecules that enclose such scaffolds and, by imposing a set of chemical and pharmacokinetic filters, obey some drug-like requirements mandatory to deal with MpND. The quantum mechanical calculations are useful to gauge the chelating properties of the selected candidate molecules by determining the structure of metal complexes and evaluating their stability constants. With the proposed strategy, commercial compounds containing N and S donor atoms in the binding sites and capable to cross the BBB have been identified and their chelating properties analyzed.     

Inorganic materials and living organisms: surface modifications and fungal responses to various asbestos forms

In a previous study several strains of soil fungi were reported to remove iron in vitro from crocidolite asbestos, a process that was envisaged as a possible bioremediation route for asbestos-polluted soils. Here, we get some new insight into the chemical basis of the fiber/fungi interaction by comparing the action of the most active fungal strain Fusarium oxysporum on three kind of asbestos fibers--chrysotile, amosite, and crocidolite--and on a surface-modified crocidolite. None of the fibers examined significantly inhibited biomass production. Even the smallest fibrils were visibly removed from the supernatant following adhesion to fungal hyphae. F. oxysporum, through release of chelators, extracted iron from all fibers; the higher the amount of iron at the exposed surface, the larger the amount removed, that is, crocidolite > amosite > chrysotile. When considering the fraction of total iron extracted, however, the ranking was chrysotile > crocidolite > amosite > heated crocidolite, because of the different accessibility of the chelators to the metal ions in the crystal structure. Chrysotile was the easiest to deplete of its metal content. Iron removal fully blunted HO* radical release from crocidolite and chrysotile but only partially from amosite. The removal, in a long-term experiment, of more iron than is expected to be at the surface suggests a diffusion of ions from the bulk solid towards the surface depleted of iron by fungal activity. Thus, if the fibers could be treated with a continuous source of chelators, iron extraction would proceed up to a full inactivation of free radical release. The fungal metabolic response of F. oxysporum grown in the presence of chrysotile, amosite and crocidolite revealed that new extracellular proteins are induced--including manganese-superoxide dismutase, the typical antioxidant defense--and others are repressed, upon direct contact with the fibers. The protein profile induced by heated crocidolite was different, a result suggesting a key role for the state of the fiber/hyphae interface in protein induction.