Switching Reversibility to Irreversibility in Glycogen Synthase Kinase 3 Inhibitors: Clues for Specific Design of New Compounds

Pérez, Daniel I.; Palomo, Valle; Pérez, Concepción; Gil, Carmen; Dans, Pablo D.; Luque, F. Javier; Conde, Santiago; Martı́nez, Ana

doi:10.1021/jm1016279

Cited by 70 publications

(77 citation statements)

References 64 publications

(165 reference statements)

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“…For example, we have a long standing interest in accessing [ 18 F]4-fluorophenacylbromide ([ 18 F]FPB, 3 ) via [ 18 F]FAP ( 2 ), due to its potential as a PET radiotracer for glycogen synthase kinase-3 (GSK-3) 40 . Typical yields of [ 18 F]FAP synthesized via traditional S N Ar chemistry (e.g.…”

Section: Resultsmentioning

confidence: 99%

Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination

Mossine

Brooks

Ichiishi

et al. 2017

Sci Rep

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In a relatively short period of time, transition metal-mediated radiofluorination reactions have changed the PET radiochemistry landscape. These reactions have enabled the radiofluorination of a wide range of substrates, facilitating access to radiopharmaceuticals that were challenging to synthesize using traditional fluorine-18 radiochemistry. However, the process of adapting these new reactions for automated radiopharmaceutical production has revealed limitations in fitting them into the confines of traditional radiochemistry systems. In particular, the presence of bases (e.g. K2CO3) and/or phase transfer catalysts (PTC) (e.g. kryptofix 2.2.2) associated with fluorine-18 preparation has been found to be detrimental to reaction yields. We hypothesized that these limitations could be addressed through the development of alternate techniques for preparing [18F]fluoride. This approach also opens the possibility that an eluent can be individually tailored to meet the specific needs of a metal-catalyzed reaction of interest. In this communication, we demonstrate that various solutions of copper salts, bases, and ancillary ligands can be utilized to elute [18F]fluoride from ion exchange cartridges. The new procedures are effective for fluorine-18 radiochemistry and, as proof of concept, have been used to optimize an otherwise base-sensitive copper-mediated radiofluorination reaction.

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Section: Resultsmentioning

confidence: 99%

Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination

Mossine

Brooks

Ichiishi

et al. 2017

Sci Rep

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“…Manzamine A specifically inhibits GSK-3β and CDK5 (the two key players in the hyperphosphorylation of tau protein in AD) with IC 50 s of 10 and 1.5 μM respectively; it is ineffective toward others kinases tested (Hamann et al, 2007). Kinetic studies indicated an ATP non-competitive inhibition regarding GSK-3 (Hamann et al, 2007) while susbstrate competitive inhibition has been recently proved experimentally (Palomo et al, 2011). …”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

“…In this case, inactivation of the enzyme is due to the formation of an irreversible covalent sulfur–carbon bond between the key cysteine 199 located at the entrance to the ATP site of GSK-3 and the HMK moiety (Perez et al, 2011). …”

Section: Organic Molecules As Gsk-3 Inhibitorsmentioning

confidence: 99%

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Eldar-Finkelman

Martı́nez

2011

Front. Mol. Neurosci.

293

278

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Inhibiting glycogen synthase kinase-3 (GSK-3) activity via pharmacological intervention has become an important strategy for treating neurodegenerative and psychiatric disorders. The known GSK-3 inhibitors are of diverse chemotypes and mechanisms of action and include compounds isolated from natural sources, cations, synthetic small-molecule ATP-competitive inhibitors, non-ATP-competitive inhibitors, and substrate–competitive inhibitors. Here we describe the variety of GSK-3 inhibitors with a specific emphasis on their biological activities in neurons and neurological disorders. We further highlight our current progress in the development of non-ATP-competitive inhibitors of GSK-3. The available data raise the hope that one or more of these drug design approaches will prove successful at stabilizing or even reversing the aberrant neuropathology and cognitive deficits of certain central nervous system disorders.

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“…Compounds 14 and 15 are reversible GSK-3 inhibitors in the low micromolar or high nanomolar range and can be used as chemical precursors for the corresponding halomethylketones (HMKs). These HMKs are irreversible inhibitors, they alkylate Cys199, which is located in the ATP binding site of GSK-3 [41]. Further maleimide derivatives are listed in Table 3.…”

Section: Small-molecule Inhibitors Of Glycogen Synthase Kinasementioning

confidence: 99%

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

Krämer

Schmidt

Monte

2012

International Journal of Alzheimer's Disease

101

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The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreased β-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidate in vivo studies and pre-/clinical trials.

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Switching Reversibility to Irreversibility in Glycogen Synthase Kinase 3 Inhibitors: Clues for Specific Design of New Compounds

Cited by 70 publications

References 64 publications

Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination

Development of Customized [18F]Fluoride Elution Techniques for the Enhancement of Copper-Mediated Late-Stage Radiofluorination

GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS

Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

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