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

Abstract

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.

Toxicology and pharmacology of synthetic organoselenium compounds: an update

“…The GPx-like activity, the molecules' ability to emulate the reaction catalyzed by the native enzyme, has been viewed, although with some controversy (Barbosa et al 2017 ; Wirth 2015 ), as the critical mechanism to design potential therapeutic agents, and it is undoubtedly the most studied property in the last decade (Ninomiya et al 2011 ; Sarma and Mugesh 2008 ). In fact, several excellent reviews dealing with GPx-like activity have been published in the literature during recent years (Bhowmick and Mugesh 2015 ; Elsherbini et al 2016 ; Orian and Toppo 2014 ; Sands et al 2018 ).…”

Selenylated-oxadiazoles as promising DNA intercalators: Synthesis, electronic structure, DNA interaction and cleavage

“…Several reports highlight their antioxidant, anti-inflammatory, antitumor, and antiviral activities [3][4][5][6]. Notably, some organoselenium compounds display the mimetic activity of these enzymes, making them attractive synthetic targets [7,8]. Considering the current pandemic of corona virus (COVID-19), a very interesting study just appeared in the literature where an organoselenium compound (Ebselen) presented the strongest antiviral effect at a concentration of 10 μM treatment in COVID-19 virus infected Vero cells [9].…”

Synthesis of alpha‐methyl selenocysteine and its utilization as a glutathione peroxidase mimic

“…Vertebrate glutathione peroxidase (GPX) is an enzyme that catalyzes the reduction of H 2 O 2 , organohydroperoxides, and lipid hydroperoxides . Multiple forms of the enzyme contain the rare amino acid selenocysteine (Sec) .…”

“…When concentrations of H 2 O 2 are elevated, such as during reoxygenation after a period of ischemia, GPX can become overwhelmed and does not reduce H 2 O 2 fast enough to prevent reperfusion injury . Thus, it is desirable to design a small molecule GPX mimic that can serve a therapeutic function for these situations of high oxidative stress …”

“…Other selenium‐containing GPX mimics have been synthesized, and some have potent GPX‐like activity including cyclic seleninate and selenenate esters, spirodioxyselenuranes, pincer selenuranes, and spirodiazaselenuranes . However, many of these compounds are expected to be toxic, are not water soluble, are unstable, or quickly lose catalytic activity in the presence of thiols …”