Modeling the Glutathione Peroxidase‐Like Activity of a Cyclic Seleninate by DFT and Solvent‐Assisted Proton Exchange

Bayse, Craig A.; Ortwine, Kristine

doi:10.1002/ejic.201300279

Cited by 17 publications

(28 citation statements)

References 44 publications

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“…Similard eactivation through selenenyl sulfide formation has also been notedw ith numerous other cyclic seleninates in subsequent studies. Recent computational investigations of this process by Bayse and Ortwine [24] were generally consistent with the mechanism indicated in Scheme 3. Their computations used methanethiol as the overall reductant and incorporated solvation effects of water.…”

Section: Cyclic Seleninate Esterssupporting

confidence: 71%

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

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2018

Chemistry A European J

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Selenium compounds play an important role in redox homeostasis in living organisms. One of their major functions is to suppress the harmful effects of hydrogen peroxide, hydroperoxides and downstream reactive oxygen species that lead to oxidative stress, which has in turn been implicated in many diseases and degenerative conditions. The glutathione peroxidase (GPx) family of selenoenzymes plays a key protective role by catalyzing the reduction of peroxides with glutathione. Considerable effort has been expended toward the discovery of small-molecule selenium compounds that mimic GPx. To date, ebselen has been the most widely studied such compound, including in several clinical trials. However, despite its proven lack of significant toxicity, it displays only moderate catalytic activity and very poor aqueous solubility. The cyclic seleninate esters and spirodioxyselenuranes have recently been investigated as potential next generation GPx mimetics, along with structurally related selenenate esters, diazaselenuranes and pincer selenuranes. Their catalytic activities, redox mechanisms and structure-activity relationships are described in this Review, along with a description and discussion of the relative merits of assays for measuring their activities.

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Section: Cyclic Seleninate Esterssupporting

confidence: 71%

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

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2018

Chemistry A European J

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“…The selenenyl sulfide pathway is energetically preferred as expected from experimental results, but the reduction to the selenol is a key bottleneck and SAPE calculations predict a significant barrier (32 kcal/mol) (29). However, in our SAPE modeling of possible mechanisms for redox cycling for ebselen (Scheme 5) and, more recently, a cyclic seleninate (84), all low barrier pathways appear to converge on the selenenyl sulfide as an intermediate. To bypass this problem, we have proposed that ebselen and other GPx mimics avoid the bottleneck of selenol regeneration by oxidizing the selenenyl sulfide to the seleninyl sulfide (Scheme 6).…”

Section: Ebselenmentioning

confidence: 53%

Modeling of Mechanisms of Selenium Bioactivity Using Density Functional Theory

Bayse

2013

ACS Symposium Series

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Selenium plays an important role in normal biological function through its incorporation into processes that protect against oxidative stress and promote thyroid function. The complex nature of the mechanisms involved has led to extensive study through computational modeling. However, density functional theory (DFT) modeling of the redox mechanisms of selenium is complicated by proton exchange processes catalyzed by the bulk solvent. To address this issue, we have used a method of microsolvation which we have dubbed solvent-assisted proton exchange (SAPE). These models include a few strategically placed water molecules to act as a proton shuttle and are able to obtain activation barriers that are in good agreement with experimental data and trends. Models that do not use these networks necessarily have higher barriers because they force the proton exchange through an 'unnatural' pathway that is not representative of the reaction as it occurs in solution. As a first approximation to solution-phase reactivity, SAPE models are more appropriate for drawing conclusions about the trends and energetics of these complex mechanisms. From these models, we have gained significant insight into the biological pathways of these compounds. In this chapter, we discuss our implementation of SAPE models for redox scavenging by various biorelevant organoselenium compounds, specifically arylselenols, seleninic acids and ebselen, and the related mechanism of cysteine. Finally, we discuss approaches to modeling additional important biochalcogen processes in the thyroid and in zinc finger proteins.

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“…Two classes of compounds that were first investigated as potential GPx mimetics by our group include the aliphatic and aromatic cyclic seleninate esters 1 12 and 2, 12c,13 as well as the corresponding spirodioxyselenuranes 3 14 and 4. 12c,13a Later studies of these types of compounds by Singh et al 15 and by Bayse and Ortwine 16 have also been reported. Certain members of both classes of compounds display >10-fold greater catalytic activity than that of ebselen.…”

Section: R a F Tmentioning

confidence: 92%

The role of methoxy substituents in regulating the activity of selenides that serve as spirodioxyselenurane precursors and glutathione peroxidase mimetics

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2016

Can. J. Chem.

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A series of o-(hydroxymethyl)phenyl selenides containing single or multiple methoxy substituents was synthesized, and the rate at which each compound catalyzed the oxidation of benzyl thiol to its disulfide with excess hydrogen peroxide was measured. This assay provided the means for comparing the relative abilities of the selenides to mimic the antioxidant selenoenzyme glutathione peroxidase. The mechanism for catalytic activity involves oxidation of the selenides to their corresponding selenoxides with hydrogen peroxide, cyclization to spirodioxyselenuranes, followed by reduction with two equivalents of thiol to regenerate the original selenide with concomitant disulfide formation. A single p-methoxy group on each aryl moiety afforded the highest catalytic activity, while methoxy groups in the meta position had little effect compared to the unsubstituted selenide, and o-methoxy groups suppressed activity. The installation of multiple methoxy groups on each aryl moiety provided no improvement. These results can be rationalized on the basis of dominating mesomeric and steric effects of the p- and o-substituents, respectively.

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Modeling the Glutathione Peroxidase‐Like Activity of a Cyclic Seleninate by DFT and Solvent‐Assisted Proton Exchange

Cited by 17 publications

References 44 publications

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

Modeling of Mechanisms of Selenium Bioactivity Using Density Functional Theory

The role of methoxy substituents in regulating the activity of selenides that serve as spirodioxyselenurane precursors and glutathione peroxidase mimetics

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