Search Results (24)

Incorporation of lanthanide (Ln) and actinide (An) ions into the human body poses significant chemotoxic and radiotoxic risks, necessitating effective decorporation strategies. This study investigates the displacement of biologically relevant ligands from trivalent ions of europium, Eu(III), and curium, Cm(III), in artificial biofluids by various complexing agents, i.e., ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid (DTPA), and spermine-based hydroxypyridonate chelator 3,4,3-LI(1,2-HOPO) (HOPO). Utilizing a modified unified bioaccessibility method (UBM) to simulate gastrointestinal conditions, we conducted concentration-dependent displacement experiments at both room and body temperatures. Time-resolved laser-induced fluorescence spectroscopy (TRLFS) supported by ²H nuclear magnetic resonance (NMR) spectroscopy and thermodynamic modelling revealed the complexation efficacy of the agents under physiological conditions. Results demonstrate that high affinity, governed by complex stability constants and ligand pK_a values, is critical to overcome cation and anion competition and leads to effective decorporation. Additionally, there is evidence that cyclic ligands are inferior to linear ligands for this application. HOPO and DTPA exhibited superior displacement efficacy, particularly in the complete gastrointestinal tract simulation. This study highlights the utility of in vitro workflows for evaluating decorporation agents and emphasizes the need for ligands with optimal binding characteristics for enhanced chelation therapies. Full article

The development of gadolinium-based magnetic resonance imaging (MRI) contrast agents (CAs) is a highly challenging and demanding research field in metal-coordination medicinal chemistry. The recognized high capacity of hydroxypyridinone (HOPO)-based compounds to coordinate Gd (III) led us to evaluate the set of physic–chemical–biological properties of a new Gd (III) complex with a hexadentate tripodal ligand (H₃L) containing three 3,4-HOPO chelating moieties attached to an anchoring cyclohexane backbone. In particular, the thermodynamic stability constants of the complex were evaluated by potentiometry, showing the formation of a highly stable (1:1) Gd-L complex (log β_GdL = 26.59), with full coordination even in an acid-neutral pH under the experimental conditions used. Molecular simulations of the Gd (III) complex revealed a minimum energy structure with somewhat-distorted octahedral geometry, involving full metal hexa-coordination by the three bidentate moieties of the ligand arms, indicating that an extra water molecule should be coordinated to the metal ion, an important feature for the CAs (and the required enhancement of water proton relaxivity). In vivo biodistribution studies with the ⁶⁷Ga complex, as a surrogate of the corresponding Gd complex, showed in vivo stability and rapid excretion from the animal body. Though deserving further investigation, these results may give an input on future perspectives towards new MRI diagnostic agents. Full article

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal Pseudomonas aeruginosa (strain PA14) administration. DIBI is a polymer with a polyvinylpyrrolidone backbone containing nine 3-hydroxy-1-(methacrylamidoethyl)-2-methyl-4(1H) pyridinone (MAHMP) residues per molecule and was given by intraperitoneal injection either as a single dose (80 mg/kg) immediately after PA14 administration or a double dose (second dose 4 h after PA14 administration). The results showed that lung NF-κBp65 levels, as well as levels of various inflammatory cytokines (TNFα, IL-1β, IL-6) both in lung tissue and bronchoalveolar lavage fluid (BALF), were significantly increased 24 h after PA14 administration. Single-dose DIBI did not affect the bacterial load or inflammatory response in the lungs or BALF. However, two doses of DIBI significantly decreased bacterial load, attenuated NF-κBp65 upregulation, reduced inflammatory cytokines production, and relieved lung tissue damage. Our findings support the conclusion that the iron chelator, DIBI, can reduce lung injury induced by P. aeruginosa, via its anti-bacterial and anti-inflammatory effects. Full article

Pseudomonas aeruginosa is one of the most common pathogens encountered in clinical wound infections. Clinical studies have shown that P. aeruginosa infection results in a larger wound area, inhibiting healing, and a high prevalence of antimicrobial resistance. Hydroxypyridinone-derived iron chelator Deferiprone (Def) and heme analogue Gallium-Protoporphyrin (GaPP) in a chitosan-dextran hydrogel (Chitogel) have previously been demonstrated to be effective against PAO1 and clinical isolates of P. aeruginosa in vitro. Moreover, this combination of these two agents has been shown to improve sinus surgery outcomes by quickly reducing bleeding and preventing adhesions. In this study, the efficacy of Def-GaPP Chitogel was investigated in a P. aeruginosa biofilm-infected wound murine model over 6 days. Two concentrations of Def-GaPP Chitogel were investigated: Def-GaPP high dose (10 mM Def + 500 µg/mL GaPP) and Def-GaPP low dose (5 mM Def + 200 µg/mL GaPP). The high-dose Def-GaPP treatment reduced bacterial burden in vivo from day 2, without delaying wound closure. Additionally, Def-GaPP treatment decreased wound inflammation, as demonstrated by reduced neutrophil infiltration and increased anti-inflammatory M2 macrophage presence within the wound bed to drive wound healing progression. Def-GaPP Chitogel treatment shows promising potential in reducing P. aeruginosa cutaneous infection with positive effects observed in the progression of wound healing. Full article

XYY-CP1106, a candidate compound synthesized from a hybrid of hydroxypyridinone and coumarin, has been shown to be remarkably effective in treating Alzheimer’s disease. A simple, rapid and accurate high-performance liquid chromatography coupled with the triple quadrupole mass spectrometer (LC-MS/MS) method was established in this study to elucidate the pharmacokinetics of XYY-CP1106 after oral and intravenous administration in rats. XYY-CP1106 was shown to be rapidly absorbed into the blood (T_max, 0.57–0.93 h) and then eliminated slowly (T_1/2, 8.26–10.06 h). Oral bioavailability of XYY-CP1106 was (10.70 ± 1.72)%. XYY-CP1106 could pass through the blood–brain barrier with a high content of (500.52 ± 260.12) ng/g at 2 h in brain tissue. The excretion results showed that XYY-CP1106 was mainly excreted through feces, with an average total excretion rate of (31.14 ± 0.05)% in 72 h. In conclusion, the absorption, distribution and excretion of XYY-CP1106 in rats provided a theoretical basis for subsequent preclinical studies. Full article

Adaptable hydrogels have been used in the biomedical field to address several pathologies, especially those regarding tissue defects. Here, we describe unprecedented catechol-like functionalized polyrotaxane (PR) polymers able to form hydrogels. PR were functionalized with the incorporation of hydroxypyridinone (HOPO) moieties into the polymer backbone, with a degree of substitution from 4 to 22%, depending on the PR type. The hydrogels form through the functionalized supramolecular systems when in contact with a Fe(III) solution. Despite the hydrogel formation being at physiological pH (7.4), the HOPO derivatives are extremely resistant to oxidation, unlike common catechols; consequently, they prevent the formation of quinones, which can lead to irreversible bounds within the matrix. The resulting hydrogels demonstrated properties lead to unique hydrogels with improved mechanical behavior obtained by metallic coordination crosslinking, due to the synergies of the sliding-ring PR and the non-covalent (reversible) catechol analogues. Following this strategy, we successfully developed innovative, cytocompatible, oxidative-resistant, and reversible crosslinked hydrogels, with the potential of being used as structural self-materials for a variety of applications, including in the biomedical field. Full article

The positron-emitting radionuclide gallium-68 has become increasingly utilised in both preclinical and clinical settings with positron emission tomography (PET). The synthesis of radiochemically pure gallium-68 radiopharmaceuticals relies on careful consideration of the coordination chemistry. The short half-life of 68 min necessitates rapid quantitative radiolabelling (≤10 min). Desirable radiolabelling conditions include near-neutral pH, ambient temperatures, and low chelator concentrations to achieve the desired apparent molar activity. This review presents a broad overview of the requirements of an efficient bifunctional chelator in relation to the aqueous coordination chemistry of gallium. Developments in bifunctional chelator design and application are then presented and grouped according to eight categories of bifunctional chelator: the macrocyclic chelators DOTA and TACN; the acyclic HBED, pyridinecarboxylates, siderophores, tris(hydroxypyridinones), and DTPA; and the mesocyclic diazepines. Full article

A novel ambidentate dipeptide conjugate (H(L1)) containing N-donor atoms of the peptide part and an (O,O) chelate at the hydroxypyridinone (HP) ring is synthesized and characterized. It is hoped that this chelating ligand can be useful to obtain multitargeted Co(III)/Pt(II) dinuclear complexes with anticancer potential. The Pd(II) (as a Pt(II) model but with faster ligand exchange reactions) binding strength of the ligand was studied in an aqueous solution with the combined use of pH-potentiometry and NMR. In an equimolar solution, (L1)⁻ was found to bind Pd(II) via the terminal amino and increasing number of peptide nitrogens of the peptide backbone over a wide pH range. At a 2:1 Pd(II) to ligand ratio, the presence of [Pd₂H_–x(L1)] (x = 1–4) species, with high stability and with the coordination of the (O,O) chelating set of the ligand, was detected. The reaction of H(L1) with [Co(tren)]³⁺ (tren = tris(2-aminoethyl)amine) indicated the exclusive binding of (L1)⁻ via its (O,O) donor atoms to the metal unit, while treatment of the resulting Co-complex with Pd(II) afforded the formation of a Co/Pd heterobimetallic complex in solution with an (NH₂, N_amide) coordination of Pd(II). Shortening the peptide backbone in H(L1) by one peptide unit compared to the structurally similar ambidentate chelator consisting of three peptide bonds resulted in the slightly more favorable formation of the N-coordinated Pd(II) species, allowing the tailoring of the coordination properties. Full article

Staphylococcus pseudintermedius is an important opportunistic pathogen causing various infections in dogs. Furthermore, it is an emerging zoonotic agent and both multidrug-resistant methicillin-resistant S. pseudintermedius (MRSP) as well as methicillin-susceptible (MSSP) strains represent an important therapeutic challenge to veterinary medicine and pose a potential threat to human health. We tested representative S. pseudintermedius clinical strains from dogs suffering from otitis externa for their susceptibilities to a panel of 17 antimicrobials compared to DIBI. DIBI, unlike antibiotics, is a novel water-soluble hydroxypyridinone-containing iron-chelating agent that deprives microbes of growth-essential iron and has been previously shown to inhibit methicillin-resistant Staphylococcus aureus (MRSA). We also characterised the strains according to whether they harbour key antibiotic resistance genes. The strains each displayed multiple antimicrobial resistance patterns; all were negative for the mecA gene and possessed the tetK and tetM genes, but they varied as to their possession of the ermB gene. However, all the isolates had similar susceptibility to DIBI with low MICs (2 µg/mL or 0.2 µM). Because the four MSSPs were equally susceptible to DIBI, subject to confirmation with additional strains, this could provide a potential non-antibiotic, anti-infective alternative approach for the treatment of antimicrobial-resistant canine S. pseudintermedius otitis. Full article

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. Full article

The increasing biomedical interest in high-stability oxidovanadium(IV) complexes with hydroxypyridinone ligands leads us to investigate the complex formation equilibria of V^IVO²⁺ 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. Full article

Hydroxypyridinones (HOPOs) have been used in the chelation therapy of iron and actinide metals. Their application in metal-based radiopharmaceuticals has also been increasing in recent years. This review article focuses on how multidentate HOPOs can be used in targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. The general structure of radiometal-based targeted radiopharmaceuticals, a brief description of siderophores, the basic structure and properties of bidentate HOPO, some representative HOPO multidentate chelating agents, radiopharmaceuticals based on HOPO multidentate bifunctional chelators for gallium-68, thorium-227 and zirconium-89, as well as the future prospects of HOPO multidentate bifunctional chelators in other metal-based radiopharmaceuticals are described and discussed in turn. The HOPO metal-based radiopharmaceuticals that have shown good prospects in clinical and preclinical studies are gallium-68, thorium-227 and zirconium-89 radiopharmaceuticals. We expect HOPO multidentate bifunctional chelators to be a very promising platform for building novel targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. Full article

Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe³⁺ at very low iron concentrations and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the radiometal gallium-68 (⁶⁸Ga). THP-peptide bioconjugates rapidly and quantitatively complex ⁶⁸Ga at room temperature, neutral pH, and micromolar ligand concentrations, making them amenable to kit-based radiosynthesis of ⁶⁸Ga PET radiopharmaceuticals. With the aim to produce an N-hydroxysuccinimide-(NHS)-THP reagent for kit-based ⁶⁸Ga-labeling and PET imaging, THP-derivatives were designed and synthesized to exploit the advantages of NHS chemistry for coupling with peptides, proteins, and antibodies. The more stable five-carbon atoms linker product was selected for a proof-of-concept conjugation and radiolabeling study with an anti-programmed death ligand 1 (PD-L1) camelid single domain antibody (sdAb) under mild conditions and further evaluated for site-specific amide bond formation with a synthesized glucagon-like peptide-1 (GLP-1) targeting peptide using solid-phase synthesis. The obtained THP-GLP-1 conjugate was tested for its ⁶⁸Ga chelating ability, demonstrating to be a promising candidate for the detection and monitoring of GLP-1 aberrant malignancies. The obtained sdAb-THP conjugate was radiolabeled with ⁶⁸Ga under mild conditions, providing sufficient labeling yields after 5 min, demonstrating that the novel NHS-THP bifunctional chelator can be widely used to easily conjugate the THP moiety to different targeting molecules (e.g., antibodies, anticalins, or peptides) under mild conditions, paving the way to the synthesis of different imaging probes with all the advantages of THP radiochemistry. Full article

Iron is essential for multiple bacterial processes and is thus required for host colonization and infection. The antimicrobial activity of multiple iron chelators and gallium-based therapies against different bacterial species has been characterized in preclinical studies. In this review, we provide a synthesis of studies characterizing the antimicrobial activity of the major classes of iron chelators (hydroxamates, aminocarboxylates and hydroxypyridinones) and gallium compounds. Special emphasis is placed on recent in-vitro and in-vivo studies with the novel iron chelator DIBI. Limitations associated with iron chelation and gallium-based therapies are presented, with emphasis on limitations of preclinical models, lack of understanding regarding mechanisms of action, and potential host toxicity. Collectively, these studies demonstrate potential for iron chelators and gallium to be used as antimicrobial agents, particularly in combination with existing antibiotics. Additional studies are needed in order to characterize the activity of these compounds under physiologic conditions and address potential limitations associated with their clinical use as antimicrobial agents. Full article

Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine—DFO; deferiprone—DFP; and deferasirox—DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis. Full article