Joanna Izabela Lachowicz

Effect of substituents on complex stability aimed at designing new iron(III) and aluminum(III) chelators.

The solution equilibria of iron(III) and aluminum(III) with two classes of hard ligands (catechol, salicylic acid and their nitro-derivatives) have been reliably studied by potentiometric, spectrophotometric and NMR spectroscopy. The effect of the nitro substituent on the binding properties of catechol and salicylic acid has been examined thoroughly. The inductive and resonance properties of the substituent that, as expected, lower the basicity of the phenolic and carboxylic groups, lead to a general decrease in both protonation and complex formation constants. This decrease causes an increase in pM of between 0.2 and 1.1pM units for the nitro-substituted salicylates and of about 4 units for 4-nitrocatechol, with a significantly higher chelating efficacy. The influence of the substituent on catechol and salicylic acid is discussed in detail on the basis of conditional constants at pH 7.4.

Toxicity of Nanoparticles

Nowadays more than thousands of different nanoparticles are known, though no well-defined guidelines to evaluate their potential toxicity and to control their exposure are fully provided. The way of entry of nanoparticles together with their specificities such as chemistry, chemical composition, size, shape or morphology, surface charge and area can influence their biological activities and effects. A specific property may give rise to either a safe particle or to a dangerous one. The small size allows nanoparticles to enter the body by crossing several barriers, to pass into the blood stream and lymphatic system from where they can reach organs and tissues and strictly interact with biological structures, thus damaging their normal functions in different ways. This review provides a summary of what is known on the toxicology related to the specificity of nanoparticles, both as technological tools or ambient pollutants. The aim is to highlight their potential hazard and to provide a balanced update on all the important questions and directions that should be focused in the near future.

Iron(III) and aluminum(III) complexes with hydroxypyrone ligands aimed to design kojic acid derivatives with new perspectives

With the aim to design new chelators for the clinical treatment of different diseases involving the trivalent metal ions Fe(III) and Al(III), we present the equilibria of kojic acid and its derivative 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one with these two metal ions. Potentiometric and spectrophotometric techniques for iron, and potentiometry and (1)H NMR for aluminum were used, supported by X-ray, electrospray ionization-mass spectrometry (ESI-MS), calorimetry and quantum chemical calculations. In this work, evidence is given on the formation of MeL, MeL(2), and MeL(3) complexes of both metal ions with kojic acid, confirmed by the X-ray structure of the FeL(3) complex, and of variously protonated Me(2)L(2) and MeL(2) complexes of 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one. The extremely good pFe value for this second ligand gives confidence to, and opens perspectives for, the search of new kojic acid derivatives.

Searching for new aluminium chelating agents: a family of hydroxypyrone ligands.

Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog.

A family of hydroxypyrone ligands designed and synthesized as iron chelators.

The use of chelating agents for iron and aluminum in different clinical applications has found increasing attention in the last thirty years. Desferal, deferiprone and deferasirox, chelating agents nowadays in use, are based on hydroxamic groups, hydroxyl-substituted pyridinones or aromatic ring systems. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives composed by two kojic units joined by linkers variously substituted. The huge advantages of these molecules are that they are easy and cheap to produce. Preliminary works on complex formation equilibria of the first group of ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The structural characterization of these new ligands is presented, and the protonation and iron(III) complex formation equilibria studied by potentiometry, UV-Visible spectrophotometry, electrospray ionization mass (ESI-MS) and (1)H NMR spectroscopy will be described and discussed.

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

AbstractOur 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. FigureAim of this paper is to illustrate the research on different classes of ligands, which are intended as possible chelating agents for the treatment of human pathologies correlated to iron and aluminium overload.

The meaning of aluminium exposure on human health and aluminium-related diseases.

Abstract The aim of this review is to attempt to answer extremely important questions related to aluminium-related diseases. Starting from an overview on the main sources of aluminium exposure in everyday life, the principal aspects of aluminium metabolism in humans have been taken into consideration in an attempt to enlighten the main metabolic pathways utilised by trivalent metal ions in different organs. The second part of this review is focused on the available evidence concerning the pathogenetic consequences of aluminium overload in human health, with particular attention to its putative role in bone and neurodegenerative human diseases.

Fluoroquinolones: A micro-species equilibrium in the protonation of amphoteric compounds

The knowledge of the speciation of fluoroquinolones is of great actuality for the implications on the activity, bioavailability and pharmacokinetics. Literature reports a number of contrasting evaluations on the existence of tautomeric forms of mono-protonated species, described by a set of protonation micro-constants. Here the protonation sequence and the related protonation constants of four representative molecules are evaluated by a combined potentiometric-spectrophotometric method. The experimental observations necessary to differentiate between a protonation scheme represented by macro-constants alone, and the one that requires the introduction of a micro-protonation scheme, are clearly delineated based on a careful analysis of experimental data and of simulated models. The role of the medium was investigated and UV-vis spectra in water- methanol solution were analyzed. The existence of the zwitterionic species alone at physiological pH in water, and an increase of the relative amount of the neutral species with the lipophilicity of the medium were remarked. This surely affects the bioavailability of FQs, with the increase of the neutral species when the molecules approach the local lipophilic environment close to the cellular membranes. NMR studies allowed the attribution of the protonation sites of the different forms. Quantum chemical evaluation of all the possible existent forms with different protonation degrees and in different sites strongly substantiates the experimental results. The study of the relevant frontier molecular orbitals completed the detailed theoretical characterization of the species.

Metal coordination and tyrosinase inhibition studies with Kojic-βAla-Kojic

Kojic acid is a natural antifungal and antibacterial agent that has been extensively studied for its tyrosinase inhibitory and metal coordination properties. Tyrosinase is a metalloenzyme with two copper ions in the active site. It is widely accepted that the tyrosinase inhibitory activity of kojic acid is related to its ability to coordinate metals. Over the past five years, we have used kojic acid to synthesize new and efficient bis-kojic acid chelators of iron and aluminium. In parallel, we investigated whether the de novo designed ligands could interfere with proper tyrosinase functioning. The present study combines our experience with inhibition and coordination studies of the new ligand: Kojic-βAla-Kojic. Research aimed at the assembly of a new potent tyrosinase inhibitor was based on the well-known crystal structure of the enzyme. Two questions were whether two kojic acids could act better than one and to what extent the length and kind of linker could ameliorate metal coordination, and inhibitory activity. Our results show that Kojic-βAla-Kojic has high affinity for Fe(III), Al(III), Zn(II), and Cu(II) and strong tyrosinase inhibitory effect and it can be proposed for use in industrial and pharmaceutical applications.

Chelation Therapy for Metal Intoxication: Comments from a Thermodynamic Viewpoint

Chelation therapy plays a prominent role in the clinical treatment of metal intoxication. In this paper the principal causes of metal toxicity are exposed, and the chemical and biomedical requisites of a chelating agent are sketched. The chelating agents currently in use for scavenging toxic metal ions from humans belong to few categories: those characterized by coordinating mercapto groups, by oxygen groups, poliaminocarboxylic acids, and dithiocarbamates. Considering that the complex formation equilibria have been studied for less than 50% of chelators in use, some reflections on the utility of stability constants are presented, together with an evaluation of ligands under the stability profile. The competition between endogenous and toxic target metal ions for the same chelating agent is furthermore examined. A thorough examination of stability constant databases has allowed to select, for each toxic metal, the ligands distinguished by the best pMe values. Even though this selection does not consider the biomedical requisites of a chelating agent, it gives a clear picture both of the pMe values that can be attained, and of the most appropriate chelators for each metal ion.