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Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

ABSTRACT: Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A_2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.

SUBMITTER: Matsumura N

PROVIDER: S-EPMC10487553 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

Matsumura Nobuko N Aoyama Koji K

International journal of molecular sciences 20230822 17

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A<sub>2A</sub> receptor antagonism and antioxidant activity, respec ...[more]

PMID: 37685879

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Project description:Reaction of amide bonds in t-butyldimethylsilyl-protected inosine, 2'-deoxyinosine, guanosine, 2'-deoxyguanosine, and 2-phenylinosine with commercially available peptide-coupling agents (benzotriazol-1H-yloxy)tris(dimethylaminophosphonium) hexafluorophosphate (BOP), (6-chloro-benzotriazol-1H-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyClocK), and (7-azabenzotriazol-1H-yloxy)trispyrrolidinophosphonium hexafluorophospate (PyAOP) gave the corresponding O(6)-(benzotriazol-1-yl) nucleoside analogues containing a C-O-N bond. Upon exposure to bis(pinacolato)diboron and base, the O(6)-(benzotriazol-1-yl) and O(6)-(6-chlorobenzotriazol-1-yl) purine nucleoside derivatives obtained from BOP and PyClocK, respectively, underwent N-O bond reduction and C-N bond formation, leading to the corresponding C6 benzotriazolyl purine nucleoside analogues. In contrast, the 7-azabenzotriazolyloxy purine nucleoside derivatives did not undergo efficient deoxygenation, but gave unsymmetrical nucleoside dimers instead. This is consistent with a prior report on the slow reduction of 1-hydroxy-1H-4-aza and 1-hydroxy-1H-7-azabenzotriazoles. Because of the limited number of commercial benzotriazole-based peptide coupling agents, and to show the applicability of the method when such coupling agents are unavailable, 1-hydroxy-1H-5,6-dichlorobenzotriazole was synthesized. Using this compound, silyl-protected inosine and 2'-deoxyinosine were converted to the O(6)-(5,6-dichlorobenzotriazol-1-yl) derivatives via in situ amide activation with PyBroP. The O(6)-(5,6-dichlorobenzotriazol-1-yl) purine nucleosides so obtained also underwent smooth reduction to afford the corresponding C6 5,6-dichlorobenzotriazolyl purine nucleoside derivatives. A total of 13 examples were studied with successful reactions occurring in 11 cases (the azabenzotriazole derivatives, mentioned above, being the only unreactive entities). To understand whether these reactions are intra or intermolecular processes, a crossover experiment was conducted. The results of this experiment as well as those from reactions conducted in the absence of bis(pinacolato)diboron and in the presence of water indicate that detachment of the benzotriazoloxy group from the nucleoside likely occurs, followed by reduction, and reattachment of the ensuing benzotriazole, leading to products.

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Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

Publications

Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

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