Molecular Factors Affecting the Complex Formation between Deferiprone (L1) and Cu(II)

Pashalidis, Ioannis; Kontoghiorghes, George J.

doi:10.1055/s-0031-1300151

Cited by 12 publications

(10 citation statements)

References 7 publications

(11 reference statements)

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“…For instance, deferiprone has been widely used for the treatment of systemic iron-related diseases and for neurological pathologies, including PD [72], due to its low molecular weight and ability to cross the blood-brain barrier. Different studies demonstrated deferiprone's ability to chelate not only iron but also copper, aluminum and zinc [73], reducing their free radical catalytic activity [74]. Moreover, multifunctional iron/copper chelating agents have been evaluated even if their clinical translation has not yet progressed [75].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Current Biomedical Use of Copper Chelation Therapy

Baldari

Rocco

Toietta

2020

IJMS

114

105

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Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.

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Section: Parkinson's Diseasementioning

confidence: 99%

Current Biomedical Use of Copper Chelation Therapy

Baldari

Rocco

Toietta

2020

IJMS

114

105

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“…It is more soluble in acid, for example in the stomach than in alkaline or neutral pH conditions. It is sparingly soluble in water at pH 7.4 (about 20 mg/ml, at 37 C) and forms red colour complexes with iron, green complexes with copper, blue complexes with uranium and colourless complexes with aluminium (38)(39)(40)(41). The affinity of L1 for iron is greater than copper, aluminium, zinc, indium, gallium and uranium and other metals at pH 7.4 (24).…”

Section: Chemical and Pharmacological Properties Of Deferipronementioning

confidence: 99%

Antioxidant targeting by deferiprone in diseases related to oxidative damage

Kontoghiorghe¹,

Kolnagou²,

Kontoghiorghes³

2014

Front Biosci

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The design of antioxidant pharmaceuticals is a major challenge for the treatment of many clinical conditions and in aging. Free radical damage (FRD) is primarily catalysed by iron catalytic centers. Most of the natural and synthetic antioxidants are ineffective in inhibiting FRD because of the achievement of low concentrations at the affected tissues. Despite that many chelators inhibit FRD in vitro and in vivo, only Deferiprone (L1) has been shown to be effective and safe in the reversal of oxidative stress related tissue damage in iron overload and other conditions such as cardiomyopathy, acute kidney disease, Friedreich ataxia etc. Deferiprone, other chelators and their combinations could be used as main, adjuvant and alternative therapies in untreated conditions eg forms of cancer, Alzheimer's and Parkinson's diseases. Therapeutic targeting in each case requires specific chelator selection based on structure/activity correlation and consideration of other parameters eg ADMET. The ability of L1 to reach extracellular and intracellular compartments of almost all tissues including the brain is a major advantage for further development and use in many clinical conditions.

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“…The design of these compounds was based on deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), which is a globally used iron-chelating drug. In vitro studies have shown that Cu II and Zn II are the most competitive metal ions against Fe III and are able to considerably affect the formation of Fe III complexes of these iron chelators (Clarke & Martell, 1992;Pashadilis & Kontoghiorghes, 2001;Li, 2019). Investigating the complexation of HPCs to Cu II and Zn II is of importance as the displacement of these essential metal ions by chelating drugs could adversely affect the biological processes dependent on these metals, potentially causing toxicity.…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of zinc(II) complexes with β-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering

May

Nys

Ching

et al. 2021

Acta Crystallogr Sect B

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The coordination properties of four hydroxypyridinecarboxylates, designed for the treatment of iron-overloading conditions as bidentate O,O′-donor ligands, have been studied with ZnII in the solid state. The coordination compounds [Zn(A1)2(H2O)2] (1), [Zn(A2)2(H2O)] (2), [Zn(A3)2(H2O)]·2H2O (3) and [Zn2(B1)4(H2O)2]·4H2O (4), where the ligands are 1-methyl-4-oxidopyridinium-3-carboxylate (A1, C7H6NO3), 1,6-dimethyl-4-oxidopyridinium-3-carboxylate (A2, C8H8NO3), 1,5-dimethyl-4-oxido-pyridinium-3-carboxylate (A3, C8H8NO3) and 1-methyl-3-oxidopyridinium-4-carboxylate (B1, C7H6NO3), have been synthesized and analysed by single-crystal X-ray diffraction. The ligands were chosen to probe (i) the electronic effects of inverting the positions of the O-atom donor groups (i.e. A1 versus B1) and (ii) the electronic and steric effects of the addition of a second methyl group in different positions on the pyridine ring. Two axially coordinated water molecules resulting in a six-coordinated symmetrical octahedron complement the bis-ligand complex of A1. Ligands A2 and A3 form five-coordinated trigonal bipyramidal complexes with one additional water molecule in the coordination sphere, which is a rarely reported geometry for ZnII complexes. Ligand B1 shows a dimeric structure, where the two Zn2+ dications have slightly distorted octahedral geometry and the pyridinolate O atom of the neighbouring complex bridges them. The coordination spheres of the Zn2+ dications and the supramolecular structures are discussed in detail. The packing arrangements of 1–3 are similar, having alternating hydrophilic and hydrophobic layers, however the similarity is broken in 4. The obtained coordination geometries are compared with their previously determined CuII analogues. The study of the individual complexes is complemented with a comprehensive analysis of ZnII complexes with oxygen donor ligands with data from the Cambridge Structural Database.

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Molecular Factors Affecting the Complex Formation between Deferiprone (L1) and Cu(II)

Cited by 12 publications

References 7 publications

Current Biomedical Use of Copper Chelation Therapy

Current Biomedical Use of Copper Chelation Therapy

Antioxidant targeting by deferiprone in diseases related to oxidative damage

Crystal structures of zinc(II) complexes with β-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering

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