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Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation.

Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation. [ABSTRACT FROM AUTHOR]

Hydroxypyridinones (HOPOs) are excellent class of chelators that have been gaining attention in the field of pharmaceutical drugs by their high chelating efficacy and specificity with different metal ions. Among all the metal ions, they exhibit a high binding affinity towards iron (III) and are clinically used as iron chelators nowadays. The HOPO family has different isomers, out of which 3,4-HOPO possesses applicability for designing drugs. The effect of methyl substitution on different positions of pyridinone ring also plays an essential role in deciding the pM values, thus describing the metal affinity. Several metal ions like Fe, Al, Cu, Zn, and some actinides are found to exhibit good chelation efficacy with HOPOs. In terms of denticity, there are various forms of HOPO. Among these, discussion on bidentate, tetradentate, hexadentate, octadentate, and dendrimers will be done here. This review systematically summarizes the various literature reports on the design and pharmacological activities of the newly developed HOPOs and their derivatives, including antibiotics, anticancer, and antineurodegeneratives. [ABSTRACT FROM AUTHOR]

Hydroxypyridinones (HPs) are recognized as excellent chemical tools for engineering a diversity of metal chelating agents, with high affinity for hard metal ions, exhibiting a broad range of activities and applications, namely in medical, biological and environmental contexts. They are easily made and functionalizable towards the tuning of their pharmacokinetic properties or the improving of their metal complex thermodynamic stabilities. In this review, an analysis of the recently published works on hydroxypyridinone-based ligands, that have been mostly addressed for environmental applications, namely for remediation of hard metal ion ecotoxicity in living beings and other biological matrices is carried out. In particular, herein the most recent developments in the design of new chelating systems, from bidentate mono-HP to polydentate multi-HP derivatives, with a structural diversity of soluble or solid-supported backbones are outlined. Along with the ligand design, an analysis of the relationship between their structures and activities is presented and discussed, namely associated with the metal affinity and the thermodynamic stability of the corresponding metal complexes. [ABSTRACT FROM AUTHOR]

While the etiology of non-familial Parkinson's disease (PD) remains unclear, there is evidence that increased levels of tissue iron may be a contributing factor. Moreover, exposure to some environmental toxicants is considered an additional risk factor. Therefore, brain-targeted iron chelators are of interest as antidotes for poisoning with dopaminergic toxicants, and as potential treatment of PD. We, therefore, designed a series of small molecules with high affinity for ferric iron and containing structural elements to allow their transport to the brain via the neutral amino acid transporter, LAT1 (SLC7A5). Five candidate molecules were synthesized and initially characterized for protection from ferroptosis in human neurons. The promising hydroxypyridinone SK4 was characterized further. Selective iron chelation within the physiological range of pH values and uptake by LAT1 were confirmed. Concentrations of 10–20 µM blocked neurite loss and cell demise triggered by the parkinsonian neurotoxicants, methyl-phenyl-pyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) in human dopaminergic neuronal cultures (LUHMES cells). Rescue was also observed when chelators were given after the toxicant. SK4 derivatives that either lacked LAT1 affinity or had reduced iron chelation potency showed altered activity in our assay panel, as expected. Thus, an iron chelator was developed that revealed neuroprotective properties, as assessed in several models. The data strongly support the role of iron in dopaminergic neurotoxicity and suggests further exploration of the proposed design strategy for improving brain iron chelation. [ABSTRACT FROM AUTHOR]

A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC 50 value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized. Image 1 • A series of hydroxypyridinone-coumarin hybrids were designed and synthesized. • Most of the hybrids displayed excellent iron ion chelating effects. • Compounds 13a and 27a exhibited significant MAO-B inhibitory activity. • Compound 27a showed good cytoprotective activity on U251 cells. • 27a ameliorated the cognitive dysfunction of scopolamine-induced AD mice. [ABSTRACT FROM AUTHOR]

This study evaluates the potential of two chelators, 1,2-dimethyl-3-hydroxypyridine-4-one (Hdpp) and 1-n-butyl-2-methyl-3-hydroxypyridin-4-one (Hnbp), to modulate cerebral rates of free radical production. The fluorometric assay for 2',7'-dichlorofluorescein, which is formed by oxidation of a nonfluorescent precursor (2',7'-dichlorofluorescein diacetate), was used to assay reactive oxygen species (ROS) production. The chelator Hdpp alone and the aluminum complexes of each chelator, Al (dpp)3 and Al (nbp)3, all inhibited basal rates of generation of ROS within a rat cerebral synaptosomal fraction. In the presence of an iron salt (1 microM FeSO4), a major enhancement of synaptosomal ROS formation was apparent. However, with the addition of an equimolar concentration of Hdpp, Al(dpp)3, or Al(nbp)3, this stimulation was completely abolished. The N-substituted-3-hydroxy-4-pyridinones have been proposed to be of clinical utility for the removal of iron or aluminum from tissues. The clinical potential of this class of chelator may be enhanced by their ability to inhibit iron-related oxidative events.

Nowadays, 3-hydroxypyridine-4-ones (HPOs) as orally active iron chelators have been introduced for the treatment of disorders associated with iron such as iron overload in thalassemia patients. In this work, a density functional theory (DFT) study was performed on a series of HPOs constituted of the different substitutions at the different positions. Structural analysis indicates that all of the HPO derivatives bind to Fe 3+ as a two-dentate mode through the oxygen atoms of the C = O groups. It is confirmed that the HPO derivative composed of three methyl groups at the different positions (3-hydroxy-1,2,5-trimethyl-4(1H) pyridinone) forms the most stable complex with Fe 3+ . Therefore, this HPO derivative acts as a better iron chelator than other ones. The vibrational frequency analysis reveals a correlation between the iron affinity constant and C = O vibrational frequency of the HPOs. Donor-acceptor interactions show an effective charge transfer from the oxygen atoms of the HPOs towards Fe 3+ . Quantum theory of atoms in molecules analysis shows the non-covalent interactions, mainly, electrostatic interactions play an important role in the complex formation of the HPOs and Fe 3+ . Finally, some linear correlations between the electron densities of the Fe − O chemical bond and interaction energy values, the vibrational frequency of the C = O bonds and electron densities of the Fe − O chemical bond were obtained and analyzed. [ABSTRACT FROM AUTHOR]

The chelating agents for Al 3+ and Fe 3+ metal cations with therapeutic applications have been considered in the recent years. In designing of the hydroxypyridinones (HPOs) as the therapeutic chelating agents for iron and aluminium overload pathologies, quantum mechanical (QM) calculations are necessary for predicting the binding energies and thermodynamic parameters of the metal−HPO complexes. Three derivatives of the HPOs called 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (DFP), 3-hydroxy-4(1H)-pyridinone (HOPO) and 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) were investigated for complexation with Fe 3+ and Al 3+ metal ions. Because of the maximum interaction between Fe 3+ and HPOs, all HPOs form stable complexes with Fe 3+ metal ion. Moreover, it was found that [Fe−P1] 2+ is a more stable complex than [Fe−DFP] 2+ and [Fe−3,4-HOPO] 2+ in the gas phase and water, confirming that P1 is the strongest selective iron chelator. The more stability of [Fe−P1] 2+ was attributed to an intramolecular hydrogen bond formation between the hydrogen atom of NH group and the oxygen atom of CH 2 OH chain. All complexes of the HPOs with Fe 3+ and Al 3+ were formed through the oxygen atoms of the C O and O H groups of the HPO. Natural bond orbital analysis showed that the interaction of the lone pair electrons of the oxygen atom of the chelator and antibonding orbitals of the Al 3+ and Fe 3+ are important in the complex formation. Topological parameters at the bond critical points confirmed the effective interaction between the Al 3+ and Fe 3+ metal ions and HPO as well as the nature of the metal−oxygen bonds. [ABSTRACT FROM AUTHOR]

A series of (3-hydroxy-4-pyridinone)-benzofuran hybrids have been developed and studied as potential multitargeting drugs for Alzheimer's disease (AD). Their design envisaged mainly to mimic the donepezil drug, a marketed inhibitor of acetylcholinesterase (AChE), and to endow the conjugate molecules with extra-properties such as metal chelation, radical scavenging and inhibition of amyloid peptide (Aβ) aggregation. Thus, a set of eleven new hybrid compounds was developed and evaluated for chemical and biological properties, in solution and in neuronal cell environment. The results are discussed in terms of the type of substituents on both main moieties and the linker size. The closest similarity with donepezil, in terms of AChE inhibitory activity, was obtained for the O -benzyl-hydroxypyridinone hybrids containing a 2-methylene linker, although still less active than the drug. However, the free-hydroxypyridinone hybrids present higher activity for the Aβ aggregation inhibition, metal chelating capacity and radical scavenging activity. Overall, some compounds demonstrated capacity to exert a multiple action by hitting three- ( 7d ) or four- ( 8d , 8f ) pathophysiological targets of AD. Furthermore, the compounds showed neuroprotective effects in neuronal cells subjected to model stressors of AD, but not significant dependence on the substituent groups. Importantly, the compounds evidenced drug-likeness properties, including good membrane permeability. [ABSTRACT FROM AUTHOR]

A series of linear poly (glycidyl methacrylate) (PGMA) polymers were synthesized via RAFT polymerization and conjugated with amine-containing 3-hydroxypyridin-4-ones (HPOs) to generate a panel of HPO-containing materials with controlled structures and specific iron-binding functions. The structures of the resulting polymers were characterized via 1 H NMR, GPC and FT-IR and their chelating capacity for iron was investigated using UV–Vis spectrophotometric titration of the iron(III) complexes. In vitro antimicrobial studies of selected ligand-containing homopolymers demonstrate that the homopolymers are capable of inhibiting the growth of methicillin-resistant Staphylococcus aureus (MRSA). It is proposed that the inhibition activity of MRSA is derived from the iron-chelating capability of the iron-binding polymers. [ABSTRACT FROM AUTHOR]

Eight lipophilic 3-hydroxy-4-pyridinones have been prepared from a microwave-mediated reaction along with the corresponding copper(II) complexes. All complexes have been obtained elementally pure and X-ray diffraction studies on two of the copper complexes have confirmed the structure of these compounds. Some of these complexes showed a promising degree of anti-mycobacterial activity against Mycobacterium tuberculosis, where activity seemed to vary by substitution at the pyridinone nitrogen atom. [ABSTRACT FROM AUTHOR]

Abstract: Hydroxypyridinones (HPs) are a family of N-heterocyclic core chelators which, based on their specific metal-coordination, easy manipulation/derivatization and biocompatibility, have been an attractive target for the development of new pharmaceutical drugs with manifold uses. Herein we describe the most recent advances reported in the literature on HPs, with a special focus on the metal chelating properties of the 3-hydroxy-4-pyridinone (3,4-HP) derivatives, and the different approaches used to functionalize these chelators to improve their biological properties, namely in terms of bioavailability and specific bio-targeting abilities. Representative examples of HPs are included, mostly for applications as chelating drugs for sequestration or passivation of metal overload or deregulated biometals, but also as metallodrugs for potential diagnostic/therapeutic purposes. These examples are discussed in terms of the chelating properties and structure–activity relationships. [Copyright &y& Elsevier]

Abstract: Two new polymeric matrices functionalized with 3-hydroxy-4-pyridinone chelating units (HP-NH-SEPH and HP-Chave been prepared and studied for their chelating ability towards a set of metal ions (e.g. Fe(III), Al(III), and Th(IV)). Both matrices demonstrated excellent ability to complex these metal ions, but HP-NH-SEPH evidenced higher chelating capacity than HP-CThe corresponding metal-complex gels presented high stability in the pH range 3–7, and their chelating capacity followed the order, Fe(III)≈Th(IV)>Al(III), in agreement with previously reported thermodynamics of the corresponding monomeric ligand–metal complexes in aqueous solution. These functionalized supports also showed capacity to be regenerated and reused. Thus, there are good perspectives for potential environmental and medical applications of these new metal sorbents. [Copyright &y& Elsevier]

Abstract: The gallium(III) complex of a new tripodal 3-hydroxy-4-pyridinone (3,4-HP) chelator has been studied in terms of its physico-chemical and in vivo properties aimed at potential application as probe for nuclear imaging. In particular, based on spectrophotometric titrations, the hexa-coordinated (1:1) gallium complex appeared as the major species in a wide physiological acid-neutral pH range and its high stability (pGa=27.5) should avoid drug-induced toxicity resulting from Ga(III) accumulation in tissues due to processes of transmetallation with endogenenous ligands or demetallation. A multinuclear (1H and 71Ga) NMR study gave some insights into the structure and dynamics of the gallium(III) chelate in solution, which are consistent with the tris-(3,4-HP) coordination and an eventual pseudo-octahedral geometry. Biodistribution and scintigraphic studies of the 67Ga(III) labelled chelate, performed in Wistar rats, confirmed the in vivo stability of the radiolabelled complex, its non interaction with blood proteins and its quick renal clearance. These results indicate good perspectives for potential application of extrafunctionalized analogues in radiodiagnostic techniques. [ABSTRACT FROM AUTHOR]

Abstract: Taking into account the recognized interest of a poly-pharmacological strategy in chelation therapy, a study of aluminium combined chelation based on 3-hydroxy-4-pyridinone (3,4-HP) compounds with complementary properties, associated to different denticity, size and extrafunctionality, is presented herein. In particular, Al-chelation has been explored, using a tetradentate IDA bis-(3,4-HP) ligand, L, and two N-glycosyl mono-(3,4-HP) derivatives (A or B). Combined complexation studies with the tetradentate and the most promising bidentate ligand (A) evidenced the formation of ternary complexes with high thermodynamic stability (Al–L–A) being the predominant species at physiological pH. In vivo studies on the ability for radiotracer (67Ga) removal from loaded mice, as a model of aluminium accumulation in body, have shown that the simultaneous administration to 67Ga-loaded mice of a mono- and a bis-(3,4-HP) chelator (e.g. A and L) leads to a rapid metal elimination from main organs and whole animal model. This may be rationalized by coadjuvation and eventual synergistic effects, due to complementary accessibility of the chelators to different cellular compartments. [Copyright &y& Elsevier]

Abstract: 3-Hydroxypyridin-4-ones selectively bind iron under biological conditions and one such compound has found application in the treatment of thalassaemia-linked iron overload. Related molecules have also been demonstrated to possess an antimalarial effect at levels which are non-toxic to mammalian cells. In an attempt to improve the efficiency of such molecules we have investigated the effect of introducing basic nitrogen centres into 3-hydroxypyridin-4-ones in an attempt to achieve targeting to lysosomes and other intracellular acidic vacuoles. Several of the compounds reported in this communication possess enhanced antimalarial activity over that of the simple hydroxypyridinone class. [Copyright &y& Elsevier]

Iron (Fe) overload diseases, such as β-thalassemia (thal) major and hemochromatosis, have been treated for several decades by chelating therapy with desferrioxamine (DFO). However, drawbacks associated with that drug led to the development of new chelating drugs. The 3-hydroxy-4-pyridinones emerged as highly effective Fe chelators, and deferiprone (L1) has been approved as a Fe chelating drug. The most recent strategy for Fe overload problems is based on the replacement of monotherapies by a combination therapy with both chelators. Following a similar chelating strategy, we present herein the results of animal tests with a combination of two different hydroxypyridinone-based chelators. Both are of the 3-hydroxy-4-pyridinone (HP) type, but with one and two HP chelating units, and extra functional groups to account for differentiation in their physicochemical and biological properties, namely chelating efficacy and bioavailability. Animal studies have shown that the simultaneous administration of this pair of HP chelators, under appropriate proportion, to metal-loaded mice, could speed up metal excretion. This may be rationalized by adjuvant and eventual synergistic effects, due to complementary accessibility of each chelator to different cellular compartments. [ABSTRACT FROM AUTHOR]

Abstract: Hydroxypyranones and hydroxypyridinones are bidentate oxygen ligands that form complexes with the majority of metal cations. These ligands and complexes are of considerable interest not only in their own right but also in relation to numerous current and potential uses and applications. This chapter reviews several areas of the chemistry of the above families of ligands and their complexes, including synthetic methods, structures, and some aspects of their solution chemistry – stability constants, solvation, partition, redox potentials, and kinetics and mechanism. It also provides an introduction to their applications in solvent extraction and analysis, to their roles in medical diagnosis and therapy, and to a variety of minor uses. It is not possible to provide anything approaching comprehensive coverage even of our selected areas, but we have tried to provide an overview of a field which extends from natural products through synthetic organic chemistry and fundamental physical inorganic chemistry to medically-relevant biochemistry. [Copyright &y& Elsevier]

In an effort to improve the zinc-chelating portion of matrix metalloproteinase (MMP) inhibitors, we have developed a family of heterocyclic zinc-binding groups (ZBGs) as alternatives to the widely used hydroxamic acid moiety. Elaborating on findings from an earlier report, we performed in vitro inhibition assays with recombinant MMP-1, MMP-2, and in a cell culture assay using neonatal rat cardiac fibroblast cells. In both recombinant and cell culture assays, the new ZBGs were found to be effective inhibitors, typically 10–100-fold more potent than acetohydroxamic acid. The toxicity of these chelators was examined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium salt cytotoxicity assays, which demonstrate that most of these compounds are nontoxic at concentrations of almost 100 μM. To address the possible interaction of sulfur-containing ZBGs with biological reductants, the reactivity of these chelators with 5,5′-dithiobis(2-nitrobenzoic acid) was examined. Finally, thione ZBGs were shown to be effective inhibitors of cell invasion through an extracellular matrix membrane. The data presented herein suggest these heterocyclic ZBGs are potent, nontoxic, and biocompatible compounds that show promise for incorporation into a new family of MMP inhibitors. [ABSTRACT FROM AUTHOR]

A series of extra-functionalized 3-hydroxy-4-pyridinone chelators of hard metal ions, containing different side-chains with peptidomimetic groups, was studied to assess the effect of those groups on the physico-chemical properties, the metal-chelating affinity and the in vivo behaviour of the compounds, in view of their potential pharmaceutical applications. Besides the synthesis of the chelators, the study of their properties in aqueous solution alone and in the presence of M 3+ ( M = Fe, Ga and Al) was performed by potentiometric/spectroscopic techniques. The octanol/water partition coefficient values of these hydroxypyridinone derivatives cover ca. 3 orders of magnitude (1.1 > log P > −2). They all form very stable tris-chelated M(III) complexes, the pFe and pGa values ranging up to five orders of magnitude. The in vivo studies showed the effect of the ligands on the biodistribution of 67Ga citrate and also of 67Ga-complexes in mice, in view of the potential use of the ligands or complexes as metal decorporating or as imaging agents, respectively. Although almost all these peptidomimetic hydroxypyridinone derivatives present very rapid clearance rate from most organs, the L-ornithine derivative (H2L9) shows to be superior to the others and as good as Deferiprone as metal decontaminant of Ga. Concerning the 67Ga complexes, the benzyl-propylamine (H2L3) shows considerable bone retention, thus suggesting its potential application as imaging agent. [ABSTRACT FROM AUTHOR]

A study of a series of bifunctional 3-hydroxy-4-pyridinone derivatives, containing side-chains with various alkyl-aryl-amine-amides as extra-functional groups, was conducted to assess the relevance of those groups to the Al-chelating affinity, the lipo-hydrophilic balance of the compounds, and67Ga biodistribution in mice, in view of their potential use as Al-decorporating agents; the results were compared with those for the drug Deferriprone. Their acid-base properties and Al-chelating affinity in aqueous solution were studied by potentiometric techniques. These ligands form very stable tris-chelated Al complexes and the non-chelating extra-groups are only responsible for small differences in the complex stability (?pAl=1.2). At physiological pH the major ligand/complex species have different charges, because of the different extent of protonation of the ligands. The introduction of the different groups induces a well-balanced stepwise-like lipo-hydrophilic character (-0.2

The neurotoxicity of aluminium is well established and so strategies for suitable aluminium chelating therapies, aimed at the treatment and/or amelioration of some neurological disorders, are of current interest. The present work describes a set of new bifunctional compounds containing a 3-hydroxy-4-pyridinone (3,4-HP) unit, as the aluminium chelating moiety, which is extra-functionalised with different alkyl-arylamine molecular segments, to account for the improvement on the biodistribution specificity of the chelating agents or the corresponding complexes. Besides the synthetic scheme, studies are performed to assess the properties of these compounds, namely in terms of lipophilicity, Al-chelating ability, speciation and in vivo 67Ga biodistribution. These studies show that the extrafunctional groups fortunately have small effects on the high Al chelating affinity of the 3,4-HP units, over a wide range of pH, but they lead to favourable changes on the lipo-hydrophilic balance of the ligands and on the complex speciation. Differences found in the biodistribution, namely the decrease of the blood-clearance rate and increase of the bone retention or the hepatobiliary excretion, seem to be mostly rationalized in terms of the increasing lipophilic character of the ligands. [Copyright &y& Elsevier]

A new tetradentate ligand having two 3-hydroxy-4-pyridinonate moieties and one carboxylate group appended to a cyclohexane backbone is reported, together with the corresponding bidentate hydroxypyridinonate pendant arm. The synthesis and characterization of these ligands, as well as their complexation properties towards the first transition series of metal ions M(II) (M=Cu, Ni, Zn) in aqueous solution, are described and discussed herein. The tetradentate ligand forms quite stable complexes with this series of metal ions and in solution, it is proved to be a much more effective chelator than the corresponding bidentate derivative. The stability constants of the complexes formed with this set of bivalent ions follow the Irving–Williams order NiZn. The carboxylic group has no interaction with the metal centre, thus remaining free for potential interaction with biological ligands (e.g. proteins). [Copyright &y& Elsevier]

The preparation of the new electrophilic iminium ester mesylate salt 5 and its reaction with primary and secondary amines have been investigated. Aniline, t-butylamine, and secondary amines react with 5 via ring opening to give the corresponding HOPO derivatives in high yields. The usefulness of this methodology has been demonstrated by the preparation of two new di-HOPO derivatives 19 and 21. This method allows the introduction of the HOPO ligand onto a variety of amine platforms without the concomitant formation of an amide bond and provides access to HOPO chelators of increased water solubility. [Copyright &y& Elsevier]

Iron overload is a serious clinical condition which can be largely prevented by the use of iron-specific chelating agents. Desferrioxamine-B, the most widely used iron chelator in haematology over the past 30 years, has a major disadvantage of being orally inactive. Consequently, the successful design of an orally active, non-toxic, selective iron chelator has become a much sought after goal. In order to identify an ideal iron chelator for clinical use, a range of specifications must be considered such as metal selectivity and affinity, kinetic stability of the complex, bioavailability and toxicity. A wide range of chelator types bind iron(III) and of these, hexa-, tri-, and bidentate are capable of providing iron(III) with the favoured octahedral environment. In this review, the comparative properties of such ligands are discussed, examples being selected from hydroxamates, aminocarboxylates, hydroxypyridinones, orthosubstituted phenols and triazoles. [Copyright &y& Elsevier]

A set of three N-carboxyalkyl 3-hydroxy-4-pyridinones has been studied as bidentate M(III) chelators (M=Fe, Al, Ga), with potential for oral administration. After preparation of the ligands, their protonation constants (log Ki) and the stability constants of their metal complexes have been determined. The distribution coefficients of these compounds, between 1-octanol and Tris buffer pH 7.4, were measured. The effect of these compounds on the biodistribution of 67Ga-citrate loaded rats was investigated and compared with that of the administered 67Ga-complexes. Results indicated that, among these chelating agents, the N-carboxyethyl derivative has the highest affinity towards this set of metal ions, irrespective of the metal, and that it could even compete with transferrin, the main Fe-plasma protein. The binding affinity and the hydrophilic character decrease with the increase in the size of the alkylic chain. The biological assays indicate that the complex formation in vivo is characterized by a high kinetics and thermodynamic stability, suggesting a competition with the transferrin. All the ligands were found to enhance the excretion of the gallium. Noteworthy is the observed Ga bone fixation, mostly with the ethyl derivative, thus suggesting the potential use of the complex as a bone seeking agent. [Copyright &y& Elsevier]

Hydroxypyridinones are a class of dioxo ligands under active development, as efficient Al (and Fe) chelators for potential medical uses. A wide range of those compounds has been designed aimed at improving their physico-chemical and pharmacokinetic properties. In this paper, we make a review on the literature results related to the design, chemistry, metal binding interaction, lipo-hydrophilic character and some biological assays of bidentate and hexadentate hydroxypyridinones. Among the different types of hydroxypyridinones, the 3-hydroxy-4-pyridinones deserved special attention because they are good orally active aluminium-chelators, and they seem to be the main candidates for replacement of desferrioxamine. The interaction of the bidentate hydroxypyridinones with Al as well as the in vivo studies have been more systematically reported than those of the hexadentate derivatives. The development of the hexadentate hydroxypyridinones is quite recent but, at physiological conditions, they have higher affinity for these M3+ ions than the bidentate derivatives. Despite only studies on hexadentate hydroxypyridinone–iron interactions are known and described herein, special attention was deserved to these results because of the in vivo/vitro similarity between the physico-chemical properties of these ions. The high Al affinity and favourable lipo-hydrophilic balance of the hydroxypyridinones suggest that their use as Al scavengers should be highly considered in future prospects. [Copyright &y& Elsevier]

The ability and site of the metal-chelating 3-hydroxypyridin-4-ones (HPs) to mobilize aluminum (Al) was assessed in Al-loaded rats using microdialysis. Four HPs with greatly varying lipophilicity were studied. One week after Al loading, microdialysis probes were implanted in the liver, a jugular vein, and the frontal cortex. An HP was given iv followed by continuous microdialysis for 5 h. Al concentrations in dialysates from the liver increased rapidly and were consistently greater than from blood, suggesting that liver was a primary site of Al chelation. Brain dialysate Al concentrations remained low, suggesting little Al chelation in the brain and little distribution of the Al HP complex into the brain. Al concentrations were determined in the main organs/tissues of a separate group of Al-loaded rats, and the percentage of the total Al body burden in each organ/tissue was calculated. The skeletal system and liver had 57 and 28% of the Al body burden, consistent with the liver as a primary site of Al chelation. The HPs chelate extravascular Al and have been shown by others to be orally active. They warrant further investigation as Al chelators. [ABSTRACT FROM AUTHOR]

In order to identify new compounds which label platelets without affecting their function, three classes of metal chelating agents have been compared with oxine for their efficiency of indium-113m platelet labelling and for their short- and long-term effects on platelet function. The 3-hydroxypyridinones (both 2-ones and 4-ones) and 3-hydroxypyranones are bidentate chelators of trivalent metal ions that are neutrally charged in the metal-complexed form and hence gain access to cells readily. The hydroxypyranone ethylmaltol has been compared with the 3-hydroxypyridin-4-one CP94 and to its structurally related lipophilic analogue CP25 as well as with the 3-hydroxypyridin-2-one, CP02. The platelet labelling efficiencies with these ligands were between 75% and 95% of that obtained with oxine, following a 12-min incubation in saline. The optimal concentration for the hydroxypyridin-2-ones and hydroxypyridin-4-ones was approximately 10 μ M compared with 100 μ M for the hydroxypyranone ethylmaltol and 60 μ M for oxine. Oxine and tropolone were found to produce significant inhibition of platelet aggregation to collagen in short-term experiments (10 min) or in longer term (18 and 42 h) ex vivo platelet cultures respectively. By contrast, ethylmaltol had no such inhibitory effects at either time interval. The relatively hydrophilic hydroxypyridin-4-one CP94 showed no inhibitory effects on collagen-induced aggregation in short-term studies, unlike the more lipid-soluble derivative CP25. These results suggest that ethylmaltol and related pyranones may have advantages over oxine and tropolone as indium platelet labelling agents where it is important not to damage platelets by the labelling process itself. [ABSTRACT FROM AUTHOR]

Platforms with liquid cores are extensively explored as cell delivery vehicles for cell-based therapies and tissue engineering. However, the recurrence of synthetic materials can impair its translation into the clinic. Inspired by the adhesive proteins secreted by mussels, liquefied capsule is developed using gelatin modified with hydroxypyridinones (Gel-HOPO), a catechol analogue with oxidant-resistant properties. The protein-based liquefied macrocapsule permitted the compartmentalization of living cells by an approachable and non-time-consuming methodology resorting to i) superhydrophobic surfaces as a processing platform of hydrogel beads, ii) gelation of gelatin at temperatures < 25 °C, iii) iron coordination of the hydroxypyridinone (HOPO) moieties at physiological pH, and iv) core liquefaction at 37 °C. With the design of a proteolytically degradable shell, the possibility of encapsulating human adipose-derived mesenchymal stem cells (hASC) with and without the presence of polycaprolactone microparticles (μPCL) is evaluated. Showing prevalence toward adhesion to the inner shell wall, hASC formed a monolayer evidencing the biocompatibility and adequate mechanical properties of these platforms for proliferation, diminishing the need for μPCL as a supporting substrate. This new protein-based liquefied platform can provide biofactories devices of both fundamental and practical importance for tissue engineering and regenerative medicine or in other biotechnology fields., (© 2021 Wiley-VCH GmbH.)

The two polynitrogen heterocyclic based hydroxypyridinone chelators. • Synthesis of new 3-hydroxy-4-pyridinone based ligands. • Excellent iron chelation properties. • Promising ligands with potent antiproliferative activity through iron depletion in vitro. Iron depletion is an efficient strategy for the development of anticancer agents. In an effort to develop efficient chelators, two new 3-hydroxy-4-pyridinone based polyazamacrocycles 1e and 2e were designed and synthesized. A preliminary study of the ligands was carried out to investigate their iron chelating capability and anti-tumor activity. Chelating kinetics revealed that the ligands exhibited excellent iron depletion capacity in neutral and acidic NH 4 OAc buffer solutions. Moreover, MTT assay showed that the new ligands displayed potent inhibitory activity in the proliferation of HepG2 cells. The attachment of hydroxypyridione units on the polyazamacrocycles promoted iron chelating capability and improved the anti-tumor activity by offering additional chelating sites and lipophilicity. These results indicate that two novel compounds may possess the therapeutic potential in the treatment of cancer through depleting cellular iron. [ABSTRACT FROM AUTHOR]

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate. [ABSTRACT FROM AUTHOR]

Hydroxypyridinones (HPs) are a family of N-heterocyclic metal chelators, which have been an attractive target in the development of a variety of new pharmaceutical drugs, due to their high metal chelating efficacy/specificity and easy derivatization to tune the desired biological properties. In fact, along the last decades, hydroxypyridinone derivatives, but mostly 3-hydroxy-4-pyridinone (3,4-HP), have been intensively used in drug design, following either a multitarget approach, in which one chelating unity is extrafunctionalized (hybridized) to enable the interaction with other important specific biological sites, or a polydenticity approach, in which more than one chelating moiety is conveniently attached to one scaffold, to increase the metal chelating efficacy. This review represents an update of the most recent publications (2014-2016) in mono-HP hybrids, namely as potential anti-Alzheimer's drugs, inhibitors of metalloenzymes and anti-microbials, and also polychelating compounds (poly- HP), in view of potential application, such as anti-microbial/biostatic agents, luminescent biosensors or diagnostic agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)