Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase

Liu, Zu Dong; Lockwood, Michelle; Rose, Sarah; Theobald, A.E.; Hider, Robert C.

doi:10.1016/s0006-2952(00)00551-7

Cited by 20 publications

(19 citation statements)

References 17 publications

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“…Indiscriminate metal chelation can induce a generalized metal deficiency with chelator-induced inhibition of metalloenzymes, metal redistribution, interference with neurotransmitter metabolism and cytotoxicity [2,[65][66][67][68][69][70][71][72][73][74]. Cuprizone (bis-cyclohexanone oxaldihydrazone) is an example of a toxic metal chelator, used to induce a reversible demyelination in rodents that mimics multiple sclerosis in humans.…”

Section: Therapeutic Strategies For Combating Metal-associated Neurodmentioning

confidence: 99%

Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

Popescu

Nichol

2010

CNS Neuroscience &Amp; Therapeutics

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The brain is rich in metals and has a high metabolic rate, making it acutely vulnerable to the toxic effects of endogenously produced free radicals. The abundant metals, iron and copper, transfer single electrons as they cycle between their reduced (Fe 2+ , Cu 1+ ) and oxidized (Fe 3+ , Cu 2+ ) states making them powerful catalysts of reactive oxygen species (ROS) production. Even redox inert zinc, if present in excess, can trigger ROS production indirectly by altering mitochondrial function. While metal chelators seem to improve the clinical outcome of several neurodegenerative diseases, their mechanisms of action remain obscure and the effects of long-term use are largely unknown. Most chelators are not specific to a single metal and could alter the distribution of multiple metals in the brain, leading to unexpected consequences over the long-term. We show here how X-ray fluorescence will be a valuable tool to examine the effect of chelators on the distribution and amount of metals in the brain.

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Section: Therapeutic Strategies For Combating Metal-associated Neurodmentioning

confidence: 99%

Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

Popescu

Nichol

2010

CNS Neuroscience &Amp; Therapeutics

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“…Generally, hydrophobic chelators inhibit lipoxygenases, therefore the introduction of hydrophilic characteristics into a chelator tend to minimise such inhibitory potential (Abeysinghe et al 1996), particularly if their introduction also induces steric interference of the chelation process at the enzyme active site (Liu et al 2002). By careful modification of physicochemical properties, iron chelators can therefore be designed which exert minimal inhibitory influence on many metalloenzymes Liu et al 2001).…”

Section: General Requirements Of Iron(iii) Complexes With Therapeuticmentioning

confidence: 99%

Metals ions and neurodegeneration

et al. 2007

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Neurodegenerative disorders include a variety of pathological conditions, which share similar critical metabolic processes such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. In this review Alzheimer's disease and Parkinson's disease are mainly discussed, with the aim of identifying common trends underlying these neurological conditions. Chelation therapy could be a valuable therapeutic approach, since metals are considered to be a pharmacological target for the rationale design of new therapeutic agents directed towards the treatment of neurodegeneration.

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“…The introduction of a hydrophilic substitutent at the 2-position of hydroxypyridinones markedly reduces the inhibitory properties, presumably due to steric interference of the chelation process at the enzyme active site. 58 In contrast lipophilicity is reported to be the dominant factor in controlling the ability of HPO chelators to inhibit mammalian tyrosine hydroxylase, 59 hydrophilic chelators (log P water/octanol À1.0) tending to be relatively weak inhibitors of this enzyme. Clearly by careful modification of physicochemical properties, iron chelators can be designed which exert minimal inhibitory influence on many metalloenzymes.…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

Design of clinically useful iron(III)‐selective chelators

Liu

Hider

2001

Medicinal Research Reviews

258

210

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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, nontoxic, 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.

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Structure–activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase

Cited by 20 publications

References 17 publications

Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

Mapping Brain Metals to Evaluate Therapies for Neurodegenerative Disease

Metals ions and neurodegeneration

Design of clinically useful iron(III)‐selective chelators

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