Design and Synthesis of Novel Pegylated Iron Chelators with Decreased Metabolic Rate

Li, Junpei; Lu, Zidong; Kong, Xiaole; Ma, Yongmin; Zhang, Xingyuan; Bansal, Sukhvinder S.; Abbate, Vincenzo; Hider, Robert C.

doi:10.4155/fmc.15.154

Cited by 4 publications

(7 citation statements)

References 23 publications

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“…However, the Log P value of 19 (Log P = −2.01) is low and so reduces the rate of penetration of membranes by nonfacilitated diffusion. Further optimization is required …”

Section: Pharmacological Applications Of Hydroxypyridinone Derivativesmentioning

confidence: 99%

Hydroxypyridinone-Based Iron Chelators with Broad-Ranging Biological Activities

et al. 2020

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Iron plays an essential role in all living cells because of its unique chemical properties. It is also the most abundant trace element in mammals. However, when iron is present in excess or inappropriately located, it becomes toxic. Excess iron can become involved in free radical formation, resulting in oxidative stress and cellular damage. Iron chelators are used to treat serious pathological disorders associated with systemic iron overload. Hydroxypyridinones stand out for their outstanding chelation properties, including high selectivity for Fe 3+ in the biological environment, ease of derivatization, and good biocompatibility. Herein, we overview the potential for multifunctional hydroxypyridinone-based chelators to be used as therapeutic agents against a wide range of diseases associated either with systemic or local elevated iron levels.

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“…However, the Log P value of 19 (Log P = −2.01) is low and so reduces the rate of penetration of membranes by nonfacilitated diffusion. Further optimization is required …”

Section: Pharmacological Applications Of Hydroxypyridinone Derivativesmentioning

confidence: 99%

Hydroxypyridinone-Based Iron Chelators with Broad-Ranging Biological Activities

et al. 2020

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“…A convenient method for the production of 2-hydroxymethyl derivatives is via a pyridine N-oxide intermediate (Scheme C) . The 2-hydroxymethyl substituent has been further utilized to conjugate additional moieties, for instance, pegylated side chains, and by conversion to the corresponding 2-aminomethyl derivatives and conversion to carboxylic acids with subsequent amidation (Scheme ). − …”

Section: Synthesis Of Hydroxypyridinonesmentioning

confidence: 99%

“…Kojic acid ( 5 ) is a convenient starting point for the synthesis of a range of 6-substituted pyridin-4-ones, for instance, pegylated derivatives . In addition, oxidation and subsequent amide formation has led to the synthesis of a wide range of analogues (Scheme A) .…”

Section: Synthesis Of Hydroxypyridinonesmentioning

confidence: 99%

“…Kojic acid ( 5) is a convenient starting point for the synthesis of a range of 6-substituted pyridin-4-ones, for instance, pegylated derivatives. 51 In addition, oxidation and subsequent amide formation has led to the synthesis of a wide range of analogues (Scheme 6A). 57 6-Substituted-2-alkyl-3-hydroxypyridin-4-ones can also be prepared in a one-pot procedure from the parent pyridinone in good yield (Scheme 6B).…”

Section: Selection Of An Optimal Bidentate Iron-binding Ligand Classmentioning

confidence: 99%

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Hydroxypyridinone Journey into Metal Chelation

et al. 2018

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Hydroxypyridinones (HOPOs) form outstanding building blocks for the development of a variety of agents in the field of metal chelation. The pyridinone ring is easily synthesized and readily converted into tetradentate, hexadentate, and octadentate chelators. There is considerable potential for the control of the stereochemistry of the resulting metal complex and hence the properties of these multidentate molecules. Their ability to rapidly bind hard metals in aqueous media has facilitated the development of efficient applications in both biological and medical contexts. In this Review, an in-depth analysis of the synthetic methodologies for HOPO-based ligands is presented, as well as the many aspects to achieve optimal biological activity. Recent advances and current challenges for the future application of HOPO structures are outlined. The present flourishing development of drug candidates and diagnostic agents based on this chemical scaffold opens access to many new applications in analytical, environmental, and clinical science.

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“…The exception to this is the C 2 amido derivatives discussed above, where N 1 alkylation sterically inhibits coplanarity of the C 2 amido group with the HP ring, disrupting hydrogen bonding and thus decreasing pFe 3+ values [ 38 ]. As such, N 1 alkyl substitution can be a useful strategy for tailoring chelators’ lipophilicity, cell permeability [ 20 ], in vivo biodistribution [ 34 ], and rates of metabolism [ 39 ] without deleterious effects on metal ion affinity. Substitution at N 1 sites has also been utilised to functionalise 3,4-HPs with fluorescent tags [ 40 ] or biological vectors [ 41 ].…”

Section: 34-hydroxypyridinones For Fe 3+ Complmentioning

confidence: 99%

Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68

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Imberti

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et al. 2017

IJMS

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Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. 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 positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.

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Design and Synthesis of Novel Pegylated Iron Chelators with Decreased Metabolic Rate

Abstract: The introduction of the pegylated substituent was found to lead to a relatively low rate of metabolism for some of the derivatives (6a, 6b, 8a and 8b), offering a possible improvement over deferiprone.

Cited by 4 publications

References 23 publications

Hydroxypyridinone-Based Iron Chelators with Broad-Ranging Biological Activities

Hydroxypyridinone-Based Iron Chelators with Broad-Ranging Biological Activities

Hydroxypyridinone Journey into Metal Chelation

Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68

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