Synthesis and Structure–Activity Correlation Studies of Secondary‐ and Tertiary‐Amine‐Based Glutathione Peroxidase Mimics

Abstract

In this study, a series of secondary- and tertiary-amino-substituted diaryl diselenides were synthesized and studied for their glutathione peroxidase (GPx) like antioxidant activities with H(2)O(2), cumene hydroperoxide, or tBuOOH as substrates and with PhSH or glutathione (GSH) as thiol cosubstrates. This study reveals that replacement of the tert-amino groups in benzylamine-based diselenides by sec-amino moieties drastically enhances the catalytic activities in both the aromatic thiol (PhSH) and GSH assay systems. Particularly, the N-propyl- and N-isopropylamino-substituted diselenides are 8-18 times more active than the corresponding N,N-dipropyl- and N,N-diisopropylamine-based compounds in all three peroxide systems when GSH is used as the thiol cosubstrate. Although the catalytic mechanism of sec-amino-substituted diselenides is similar to that of the tert-amine-based compounds, differences in the stability and reactivity of some of the key intermediates account for the differences in the GPx-like activities. It is observed that the sec-amino groups are better than the tert-amino moieties for generating the catalytically active selenols. This is due to the absence of any significant thiol-exchange reactions in the selenenyl sulfides derived from sec-amine-based diselenides. Furthermore, the seleninic acids (RSeO(2)H) derived from the sec-amine-based compounds are more stable toward further reactions with peroxides than their tert-amine-based analogues.

Modeling of Mechanisms of Selenium Bioactivity Using Density Functional Theory

“…Comparison of the SAPE results to experimental trends are difficult because various conditions are used by different researcher in their kinetics studies. However, our conclusions appear to be in agreement with a series of paper on amino-substituted diselenides (69,70). Interesting, and a problem for future experimental studies, is the possibility that alternate pathways for catalytic redox scavenging open due to the high barrier to step 3 of the GPx cycle.…”

Synthesis, characterization, structures and antioxidant activity of nicotinoyl based organoselenium compounds

“…NMR spectra were recorded on a Bruker Avance-II 300 MHz spectrometer operating at 300. 13 To a THF solution of Na 2 Se 2 (prepared from selenium metal (3.50 g, 44.32 mmol) and sodium borohydride (1.75 g, 46.26 mmol) in refluxing THF (100 ml) under nitrogen), solid 2-chloronicotinic acid (6.96 g, 44.17 mmol) was added with stirring and the contents were refluxed for 3 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was treated with water (50 ml). The aqueous phase was extracted with chloroformemethanol (80:20).…”

“…The SeeSe distance in 4 (2.3916(12) Å) is slightly longer than those reported in various pyridyl diselenides such as 2,2-dipyridyldiselenide (2.2969(9) Å) [ [13]. The pyridyl nitrogen atoms are in cis, cis position relative to Se(1)eSe(1) 0 group.…”

“…IIeIV) [7e9], (ii) compounds exhibiting weak intra-molecular Se/N or Se/O interactions (e.g. VeVIII) reported by Wilson [10], Tomoda [11], Mugesh [12,13], Singh [6,14], Wirth [15] and Jain [16] (iii) heterocyclic diselenides, e.g. 2-pyridyl diselenide (IX) [17] and (iv) compounds, both mono and diselenides, derived from alky groups bearing eOH, eNH 2 , eCOOH substituent at terminal positions (XeXIII) [18e21] (Scheme 1).…”

Catalytic application of selenium and tellurium compounds as glutathione peroxidase enzyme mimetics

“…The methoxy substituents also protect the selenium in the selenenic acid intermediates from overoxidation to seleninic acids or irreversible inactivation to selenonic acid derivatives. Later, the same group also compared the previously mentioned diselenides possessing a tertiary amino group 15a-c with diselenides assembled with secondary amino substituents 17a-c. 18 Their findings revealed that replacement of the tert-amino groups in benzylamine-based diselenides by sec-amino moieties drastically enhances the catalytic activity of the studied compounds. This distinct behavior was attributed to differences in the stability and reactivity of some of the key intermediates which account for the GPx like activity.…”