Enhanced Glutathione Peroxidase Activity of Water-Soluble and Polyethylene Glycol-Supported Selenides, Related Spirodioxyselenuranes, and Pincer Selenuranes

Abstract

Diaryl selenides containing o-hydroxymethylene substituents function as peroxide-destroying mimetics of the antioxidant selenoenzyme glutathione peroxidase (GPx), via oxidation to the corresponding spirodioxyselenuranes with hydrogen peroxide and subsequent reduction back to the original selenides with glutathione. Parent selenides with 3-hydroxypropyl or 2,3-dihydroxypropyl groups produced the novel compounds 10 and 11, respectively, with greatly improved aqueous solubility and catalytic activity. The phenolic derivative 28 displayed similarly ameliorated properties and also modest radical-inhibiting antioxidant activity, as evidenced by an assay based on phenolic hydrogen atom transfer to the stable free radical DPPH. In contrast, several selenides that afford pincer selenuranes (e.g., 20 and 21) instead of spiroselenuranes upon oxidation showed inferior catalytic activity. Several selenide analogues were attached to polyethylene glycol (PEG) oligomers, as PEG substituents can improve water solubility and bioavailability, while retarding clearance. Again, the PEG derivatives afforded remarkable activity when oxidation generated spirodioxyselenuranes and diminished activity when pincer compounds were produced. Several such compounds proved to be ca. 10- to 100-fold catalytically superior to the diaryl selenides and their spirodioxyselenurane counterparts investigated previously. Finally, an NMR-based assay employing glutathione in D2O was designed to accommodate the faster reacting water-soluble mimetics and to more closely duplicate in vivo conditions.

Chain‐Breaking Phenolic 2,3‐Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies

“…In fact, only very few selenium antioxidants are multifunctional in the senset hat they can act both chain-breaking and peroxide-decomposing. [15,28] Initially, we were largely ignorant about the mechanism responsible for quenching of peroxyl radicals by 8.I nl ight of the resultsp resented in this paper,c onventionalH -atom transfer from phenol to the peroxyl radicald oes not seem to be an important reaction with compounds 9-11.R ather,a nO -atom transfer mechanism, similart ot he one proposed for alkyltelluro phenols, is likelyt ob eo perative. The close (ortho)a rrangement of OH and Se has many advantages.…”

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

“…[51] While several of the cyclic seleninates and spiroselenuranes describeda bove have improveda ctivity compared to ebselen in the indicated assays,m ost display equally poor solubility in water.I no rder to improves olubility,s elenides 36 and 38 were prepared, representing the reduced form of spiroselenuranes 37 and 39,r espectively. [52,53] These compounds retain one arylseleniumb ond in order to resist metabolic conversion into toxic inorganic species, but display much improved solubility properties. Thus, selenides 36 proved soluble in 5% ethanolwater,w hile the additional hydroxyl group in compounds 38 renderedt hem freely soluble in water alone.…”

“…Catalyticactivities of water-soluble selenides 36 and 38. [52] Catalyst [a] Position of methoxy group [b] HPLC assay t www.chemeurj.org 40 both displayed activity more than 100 times greater than that of ebselen under these conditions. Ac ommon method for improving the bioavailability,m etabolic stabilitya nd aqueous solubility of drugs is by attaching them to ap olyethyleneg lycol (PEG) support.…”

“…[35] As part of the investigation of water-soluble spirodioxyselenuranes, several pincer selenuranes were also prepared, and Figure 13). [52]…”

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

“…11,12 However, ebselen is not water soluble, making rapid intravenous administration impossible, and has shown cellular toxicity in some studies. [13][14][15] Other selenium-containing GPX mimics have been synthesized, and some have potent GPX-like activity including cyclic seleninate and selenenate esters, [16][17][18][19][20][21] spirodioxyselenuranes, [22][23][24] pincer selenuranes, 22 and spirodiazaselenuranes. 25,26 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.…”