Role of Hydrogen Bonding by Thiones in Protecting Biomolecules from Copper(I)-Mediated Oxidative Damage

Abstract

The sulfur-containing antioxidant molecule ergothioneine with an ability to protect metalloenzymes from reactive oxygen species (ROS) has attracted significant interest in both chemistry and biology. Herein, we demonstrated the importance of hydrogen bonding in S-oxygenation reactions between various thiones and H2O2 and its significance in protecting the metal ion from H2O2-mediated oxidation. Among all imidazole- and benzimidazole-based thiones (1–10), ImMeSH (2) showed the highest reactivity toward H2O2almost 10 and 75 times more reactive than N,N′-disubstituted ImMeSMe (5) and BzMeSMe (10), respectively. Moreover, metal-bound ImMeSH (2) of [TpmCu­(2)]+ (13) was found to be 51 and 1571 times more reactive toward H2O2 than the metal-bound ImMeSMe (5) of [TpmCu­(5)]+ (16), and BzMeSMe (10) of [TpmCu­(10)]+ (21), respectively. The electron-donating N–Me substituent and the free N–H group at the imidazole ring played a very crucial role in the high reactivity of ImMeSH toward H2O2. The initial adduct formation between ImMeSH and H2O2 (ImMeSH·H2O2) was highly facilitated (−23.28 kcal mol–1) due to the presence of a free N–H group, which leads to its faster oxygenation than N,N′-disubstituted ImMeSMe (5) or BzMeSMe (10). As a result, ImMeSH (2) showed a promising effect in protecting the metal ion from H2O2-mediated oxidation. It protected biomolecules from Cu­(I)-mediated oxidative damage of through coordination to the Cu­(I) center of [TpmCu­(CH3CN)]+ (11), whereas metal-bound ImMeSMe or BzMeSMe failed to protect biomolecules under identical reaction conditions.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

“…Copper is a cofactor for Cu/Zn-superoxide dismutase and plays a key role in scavenging ROS. An imbalanced homeostasis of copper can induce oxidative stress and cause ROS overproduction by Fenton and Haber-Weiss reactions [82]. Interferes with the bidirectional and copper-dependent communication between neurons and astrocytes could eventually lead to various brain diseases.…”

The biology of ergothioneine, an antioxidant nutraceutical

“…Oxidative stress can be defined and measured in many ways (461)(462)(463)(464)(465)(466)(467)(468) , but is broadly taken to involve a dysregulation in the various redox systems of the organism of interest, coupled to the production of various 'reactive oxygen species', principally peroxide, superoxide, hydroxyl radical, and singlet oxygen. ERG has been shown to decrease oxidative stress in the liver and kidney of rats (469) , rescued cells from β-amyloid-induced apoptotic death (231) , protected against palmitic acid-induced cell death (470) , mercuric chloride-induced cellular dysfunction (471) , and prevented Cu-induced oxidative damage to DNA (472,473) . It is protective against the oxidation of various kinds of molecule (251,474) , including astaxanthin (475) , and accumulates in a guinea-pig model of non-alcoholic fatty liver disease (476) , massively so in mouse models of myocardial infarction and heart failure (477) , and in a rat model of optic nerve crush (478) .…”

8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

“…56 Cu is a cofactor of an essential antioxidant enzyme, Cu/Zn-superoxide dismutase 1 (SOD1), plays key role in radical scavenging and anti-inflammatory functions. 60 Decreased expression of SOD1 was observed in the AD patients which indicates the impaired capacity of the brain to cope with the excessive ROS. 61 This may be due to the highly accumulation of Cu ion within the Aβ plaque that consequently leads to deprived amount of Cu ions in other required brain areas.…”