Synthesis of Water-Soluble Vinyl Selenides and Their High Glutathione Peroxidase (GPx)-Like Antioxidant Activity

Abstract

A convenient procedure for the synthesis of novel bis-(1-hydroxymethyl-2-halo-3-hydroxy-1-propylene) selenides has been developed. On oxidation these compounds form novel seleno-spiro compounds and their glutathione peroxidase mimetic activity has been studied. They promote the hydrogen peroxide oxidation of phenylmethanethiol to the corresponding disulfide via a catalytic cycle.Key words: alkynes, selenium, oxidation, spiro compounds, diols Glutathione peroxidase (GPx) is a selenoenzyme that protects cells by catalyzing the reduction of peroxides with the stoichiometric reductant glutathione. 1The enzyme catalytic site includes a selenocysteine residue in which the selenium undergoes a redox cycle involving the selenolate anion as the active form, which reduces hydroperoxides. The selenol is first oxidized to a selenenic acid EnzSeOH, which reacts with reduced glutathione GSH to form the selenyl sulfide EnzSeSG. A second glutathione then regenerates the active form of the enzyme by attacking the EnzSeSG to form the oxidized glutathione GSSG. The overall catalytic cycle is depicted in Figure 1. Ebselen [2-phenyl-1,2-benzoisoselenazol-3(2H)-one] has been known as a mimetic of glutathione peroxidase (GPx), able to interact with active oxygen species present in living cells. [3][4][5][6] However, its use under nonenzymic conditions as a catalyst for hydrogen peroxide oxidation of thiols to disulfides gave poor results. Recently, Back et al. 7,8 have demonstrated the exceptional glutathione peroxidase-like activity of the simple bis(3-hydroxypropyl) selenide and the unexpected role of its oxidation product, spirodioxaselenanone, as an intermediate in the catalytic redox cycle for GPx.In view of the known role of organoselenium compounds in biological systems, [9][10][11][12] in addition to their unique characteristics in organic synthesis, 13 the design and synthesis of novel organoselenium compounds with potential biological activity constitutes an ongoing challenge. Recently, we have found that in situ prepared selenium dichloride, readily obtained from elemental selenium and sulfuryl chloride, 14 undergoes smooth 1,2-addition to the triple bond of various propargylic alcohols resulting in the formation of symmetrical (Z,Z)-bis(1-hydroxymethyl-2-chlorovinyl) selenides 1 in high yields and in completely regio-and stereospecific manner (Scheme 1). 15,16Of special mechanistic interest is the observed syn-addition and anti-Markovnikov orientation.Scheme 1 Regio-and stereospecific synthesis of functionalized divinyl selenides Inspired by the above findings, we applied our regio-and stereospecific SeCl 2 addition protocol in the planned preparation of novel GPx-mimetics of spirodioxaselenurane type. 8Those divinyl selenides formed by syn-addition of SeCl 2 to the triple bond, which do not bear a vicinal hydrogen capable of cis elimination, gave stable selenoxides 2a,b and selenone 3 in good yield upon oxidation with tert-butyl hydroperoxide or with 2 equivalents of MCPBA, respectively (Scheme 2). The divinyl s...

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

“…Braverman et al . investigated the GPx‐like activity of the water‐soluble unsaturated spirodioxyselenuranes 47 and its precursor selenides 46 , which exhibited higher activity than ebselen.…”

Zero-, one-, two- and three-dimensional supramolecular architectures sustained by Se…O chalcogen bonding: A crystallographic survey

“…The interactions selenium(VI) species form with oxygen reflect more conventional Lewis acid-Lewis base interactions. There are 18 selenium(IV) species, 33 – 50 [100] , [102] , [103] , [104] , [105] , [106] , [107] , [108] , [109] , [110] , [111] , [112] , [113] , [114] , [115] , and five selenium(VI) species, 51 – 55 [116] , [117] , [118] , [119] , forming Se … O contacts leading to zero-dimensional aggregates, with the chemical diagrams for the interacting species in these shown in Fig. 4 .…”

“…The majority of the selenium(IV) compounds form centrosymmetric dimers, indeed 14 of the 18 crystals feature this motif, and each of these is constructed about a four-membered { … Se–O} 2 synthon. Compounds 33 [102] , 34 [103] , 35 – 37 [104] conform to the general formula R(R′)Se O. The dimeric aggregate for 34 , being representative for this series, is shown in Fig.…”

Oxidation of E,E‐bis(3‐bromo‐1‐chloro‐1‐propen‐2‐yl) chalcogenides and use of E,E‐bis(3‐bromo‐1‐chloro‐1‐propen‐2‐yl)sulfone in heterocyclization with primary amines

“…It should be noted that the syntheses of substituted bis(1‐chloro‐1‐propen‐2‐yl) selenoxides remain solitary in the literature. For example, it was reported that the oxidation of adducts of propargylic alcohol and selenium dichloride proceeded via the intermediate formation of unstable bis(1‐chloro‐1‐propen‐2‐yl)selenoxides, which further cyclized across the hydroxyl groups to give selenospiro compounds. Similar selenoxides were prepared by hydrolysis of bis(1‐chloro‐1‐propen‐2‐yl)selenium dichlorides, adducts of propargylic alcohols and selenium tetrachloride, with aqueous solution of sodium hydrocarbonate .…”