Effect of Methoxy Substituents on the Activation Barriers of the Glutathione Peroxidase-Like Mechanism of an Aromatic Cyclic Seleninate

Abstract

Density functional theory (DFT) models including explicit water molecules have been used to model the redox scavenging mechanism of aromatic cyclic seleninates. Experimental studies have shown that methoxy substitutions affect the rate of scavenging of reactive oxygen species differently depending upon the position. Activities are enhanced in the para position, unaffected in the meta, and decreased in the ortho. DFT calculations show that the activation barrier for the oxidation of the selenenyl sulfide, a proposed key intermediate, is higher for the ortho methoxy derivative than for other positions, consistent with the low experimental conversion rate.

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

“…Furthermore,i ntroductiono fasecond or third methoxy group afforded no furthera dvantage (Table 1). Computational work by Bayse and Shoaf [31] showedt hat the observed differences stemming from o-, m-o rp-substitution were most pronouncedi nt he step where furthero xidation of the corresponding selenenyl sulfide intermediates occurs. In addition, Singh et al [32] demonstrated that the presenceo fan ortho nitro group in 10 has as alutary effect on GPx-like activity.T his was attributed to its ability to coordinate with the sele- Table 1.…”

“…Furthermore, introduction of a second or third methoxy group afforded no further advantage (Table ). Computational work by Bayse and Shoaf showed that the observed differences stemming from o ‐, m ‐ or p ‐substitution were most pronounced in the step where further oxidation of the corresponding selenenyl sulfide intermediates occurs. In addition, Singh et al .…”

Non-covalent interactions in the glutathione peroxidase active center and their influence on the enzyme activity

“…Over the last two decades, significant attention was paid by researchers to the development and synthesis of low-molecular-weight organoselenium compounds that functionally mimic the active center of the GPx-1 enzyme. [6][7][8][9][10][11][12][13] In all cases, the activation of the reactivity of the selenolic fragment -SeH was performed by introducing the selenium atom into additional interactions. Such experimental and computational studies of mechanisms of catalytic reactions involving model compounds have shown that transformation pathways vary significantly in a series of similar compounds with different substituents.…”

Computational Modeling of the Catalytic Cycle of Glutathione Peroxidase Nanomimic

“…25 SAPE procedure was also used by Bayse group as the network of explicit solvent molecules to facilitate the proton transfer reaction. 26 In the micro solvent SAPE model, the heavy atom proton donor/acceptor is connected to a number of solvent molecules by building a hydrogen-bonding network to supply a direct proton shuttle pathway. 27 The mechanisms of the catalytic cycle activity of the GPx mimic such as ebselen have been investigated theoretically 28 by Pearson and Boyd in 2008 and experimentally 12 by Bhabak and Mugesh in 2010.…”

“…SAPE procedure was also used by Bayse group as the network of explicit solvent molecules to facilitate the proton transfer reaction . In the micro solvent SAPE model, the heavy atom proton donor/acceptor is connected to a number of solvent molecules by building a hydrogen-bonding network to supply a direct proton shuttle pathway …”