Abstract
The present chapter describe a series of synthetic organoselenium compounds such as ebselen analogues, diaryl selenides, spirodioxyselenurane, spirodiazaselenuranes and its Glutathione peroxidise (GPx) catalytic activity. These ebselen related compounds either by modifying the basic structure of ebselen or incorporating some structural features of the native enzyme, a number of small-molecules of selenium compounds as functional mimics of GPx are discussed. In addition to this, spirodioxyselenuranes and spirodiazaselenuranes are important class of hypervalent selenium compounds, whose stability highly depends on the nature of the substituents attached to the nitrogen atom. The glutathione peroxidase (GPx) mimetic activity of all the selenium compounds showed significantly by facilitating the oxidation of the selenium centre. In contrast to this, ebselen analogue shows significant antioxidant activity compared with spirodiazaselenuranes and its derivatives.
Keywords
- spirodiazaselenuranes
- antioxidant activity
- selenoenzymes
- ebselene
1. Introduction
Selenium has been discovered by the Swedish scientist Jons Jakob Berzelius in 1818. The chemistry of selenium, the next element to sulfur in the chalcogen group, is very less explored as compared to the chemistry of sulfur [1]. The diethyl selenide was synthesized by Lowig in 1836 and it was obtained in pure form in 1869 ass first synthetic selenium compound [2, 3]. Selenium chemistry was initially mainly focused on the synthesis of simple diselenides (RSeSeR), selenols (RSeH) etc. However, due to the unpleasant odor of selenols and aliphatic selenides, and also its toxicity the selenium chemistry faced a serious setback. Furthermore, due to toxicity of selenium was associated with diseases such as liverstock disease [4], intoxication in experimental animals [5, 6, 7] etc., therefore, it was considered a toxic element. In 1954 by Pinsent was established with the beneficial effect of selenium for living organisms the discovery that certain bacteria grew faster in selenium fortified medium [8]. However, the exact role of selenium responsible for the growth of bacteria was not clear. Almost after 20 years of this discovery, in 1973, it was found that two bacterial enzymes, formate dehydrogenase and glycine reductase contain selenium in their active sites [9, 10]. Flohe and co-workers was discovered almost at the same time the importance of selenium to mammals [11]. They found that the mammalian enzyme glutathione peroxidase (GPx), contains a selenocysteine residue in its active site. Nowadays the major selenoenzymes discovered to date include formate dehydrogenases [12], hydrogenases [13, 14, 15, 16], glycine reductase [17] iodothyronine deiodinases (ID) [18, 19, 20, 21, 22], thioredoxin reductases (TrxR) [23, 24, 25, 26], selenophosphate synthetase [27], and selenoprotein P [28, 29], glutathione peroxidase (GPx) [30, 31, 32, 33].
1.1 Glutathione peroxidase
Glutathione peroxidase (GPx) an mammalian enzyme, contains selenocysteine residue in its active site, For the last four decades, an extensive research has been carried out on the mammalian antioxidant enzymes GPx [34]. The cGPx utilizes glutathione (GSH) as reducing substrate exclusively for the reduction of H2O2 and organic hydroperoxides such as
The crystal structure of the seleninic acid form of human pGPx also indicates that Gln79 and Trp153 are located within hydrogen bonding distance of the selenium atom (Figure 1). These residues appear to play an important functional role in their catalytic mechanisms.
A catalytic cycle of GPx (Figure 2) starts with the oxidation of the selenol (ESeH) moiety of Sec residue by peroxide to generate the selenenic acid (ESeOH) [37, 38], which reacts with cellular thiol (glutathione, GSH) to generate a selenenyl sulfide intermediate (ESeSG).
Another equivalent of GSH cleaves the -Se-S- bond in the selenenyl sulfide intermediate to regenerate the selenol with elimination of glutathione disulfide (GSSG). The cellular level concentration of GSH is maintained by glutathione reductase (GR) [39], which reduces GSSG to GSH by using NADPH as cofactor. The overall catalytic mechanism, two equivalents of NADPH is consumed to reduce one equivalent of peroxide. At very high concentrations of hydroperoxide the selenium centre in GPx may be overoxidized to produce seleninic acid (ESeO2H) and selenonic acid (ESeO3H). Whereas the oxidation of selenenic acid to seleninic acid is reversible in the presence of GSH, the further oxidation to selenonic acid may inactivate the enzyme.
2. Mimics and models of glutathione peroxidase
2.1 Ebselen analogues as GPx mimics/models
Synthetic selenium compounds with significant GPx activity have potential therapeutic applications (Figure 3). The first synthetic compound that has been shown to mimic the GPx activity was ebselen ([2-phenyl-1,2-benzisoselenazole-3)-(2
In literature there were a several animal model studies have demonstrated that ebselen reduces oxidative stress in ischemia-reperfusion in heart and that it exhibits promising neuroprotective effect in brain. In addition to this, ebselen can be toxic to cells suggested in recent evidences. It has been shown that ebselen inhibits certain cell growth and induces apoptosis. However, the mechanism underlying the toxicity of ebselen is not known, the cellular glutathione (GSH) level appears to be depleted by ebselen. The GSH depletion increases the susceptibility of cells to oxidant injury as the reduced GSH is important for cell survival.
After the discovery that ebselen exhibits significant antioxidant activity by mimicking the active site of GPx, much attention has been devoted to the design and synthesis of novel analogues of ebselen. The ebselen homolog
According to this mechanism the corresponding selenenyl sulfide is mainly the reaction of ebselen
Back and co-workers [46], reported the catalytic cycle of di(3-hydroxy-propyl) selenide
The reaction of
3. Spirochalcogenuranes
3.1 Spirodioxyselenuranes/spirodiazaselenurane and its analogues as GPx mimics/models
Lesser and Weiss in 1914 reported the first example of a spirodioxyselenurane
In continuation selenium compounds in 2004 Back and co-workers reported for the first time that spirodioxyselenurane and its tellurium analogue exhibit very good antioxidant activity by mimicking the glutathione peroxidase (GPx) enzyme which protects the organism from oxidative damage by catalyzing the reduction of peroxides using thiol as the cofactor [47, 56]. Subsequently, a series of spirodioxyselenuranes with different stereochemistry and ring size has been reported [50, 54]. Very recently, we have reported the first example of a hydrolytically stable spirodiazaselenurane
3.2 Glutathione peroxidase (GPx) activity
Back and co-workers reported that spirodioxyselenurane
The nucleophilic attack of the thiol at the selenium center may produce the intermediates
3.3 Mechanism of spirocyclization
Detailed mechanistic studies of spirodiazaselenuranes and structural characterization were carried out by using 77Se NMR spectroscopy. It was observed in the previous studies the presence of aromatic substituents cyclization process is very rapid at room temperature (25°C) on the nitrogen atoms as apical position [58]. To detect intermediates at room temperature (25°C) the cyclizations of the selenides to the corresponding spiro compounds were too fast. However, the formation of selenoxide could be observed when the cyclization is blocked by replacing the N-H moiety in compound
However, it was observed when a solution of compound
4. Conclusions
In conclusion, a series of ebselen, diaryl selenides and spirodiazaselenuranes and its glutathione peroxidase (GPx) activity were discussed. A detailed mechanistic study suggests that the spirocyclization occurs
Acknowledgments
This study was supported by the Department of Science and Technology (DST), New Delhi. DSL thanks the UGC for the award of Dr. D. S. Kothari postdoctoral research fellowship and Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore. In addition author thanks to Prof. CNR Rao Research Centre Basaveshwar Science College, Bagalkot for support and encouragements.
References
- 1.
Berzelius JJ. Undersökning af enny Mineral-kropp, funnen ide orenare sorterna af detvid Fahlun tillverkade svafle, Discovery of Selenium. Afhandlingar i Fysik, Kemi och Mineralogi. 1818; 6 :42 - 2.
Löwig CJ. Poggendorff’s Ueber schwefelwasserstoff-und selenwasserstoffäther (about hydrogen sulfide and selenium hydrogen ether). Annals of Physics. 1836;37 :552 - 3.
Rathke B. Ueber das Selenmercaptan. Justus Liebigs Annalen der Chemie. 1869; 152 :211 - 4.
Hutton JG. The correlation of certain lesions in animals with certain soil types. Journal of the American Chemical Society. 1931; 23 :1076 - 5.
Franke KW. A toxicant occurring naturally in certain samples of plant foodstuffs. I. Results obtained in preliminary feeding trials. The Journal of Nutrition. 1934; 8 :597 - 6.
Franke KW, Potter VR. A new toxicant occurring naturally in certain samples of plant foodstuffs. IX. Toxic effects of orally ingested selenium. The Journal of Nutrition. 1934; 8 :615 - 7.
Franke KW, Painter EP. A new toxicant occurring naturally in certain samples of plant foodstuffs. XIV. The effect of selenium containing foodstuffs on growth and reproduction of rats at various ages. The Journal of Nutrition. 1936; 10 :599 - 8.
Pinsent J. The need for selenite and molybdate in the formation of formic dehydrogenase by members of the coli-aerogenes group of bacteria. The Biochemical Journal. 1954;57 :10 - 9.
Andreesen R, Ljungdahl L. Formate dehydrogenase of Clostridium thermoaceticum : Incorporation of Selenium-75, and the effects of selenite, Molybdate, and tungstate on the enzyme. Journal of Bacteriology. 1973;116 :867 - 10.
Turner DC, Stadtman TC. Purification of protein components of the clostridial glycine reductase system and characterization of protein a as a selenoprotein. Archives of Biochemistry and Biophysics. 1973; 154 :366 - 11.
Flohe L, Günzler EA, Schock HH. Glutathione peroxidase-selenoenzyme. FEBS Letters. 1973; 32 :132 - 12.
Boyington JC, Gladyshev VN, Khangulov SV, Stadtman TC, Sun PD. Crystal structure of formate dehydrogenase H: Catalysis involving Mo, molybdopterin, selenocysteine, and an Fe4S4 cluster. Science. 1997; 275 :1305 - 13.
Wilting R, Schorling S, Persson BC, Bock A. Selenoprotein synthesis in archaea: Identification of an mRNA element of Methanococcus jannaschii probably directing selenocysteine insertion. Journal of Molecular Biology. 1997;266 :637 - 14.
Garcin E, Vernede X, Hatchikian EC, Volbeda A, Frey M, Fontecilla-Camps JC. The crystal structure of a reduced[NiFeSe] hydrogenase provides an image of the activity catalytic center. Structure. 1999; 7 :557 - 15.
Pfeiffer M, Bingemann R, Klein A. Fusion of two subunits does not impair the function of a [NiFeSe]-hydrogenase in the archaeon Methanococcus voltae Eur . Journal of Biochemistry. 1998;256 :447 - 16.
Wagner M, Sonntag D, Grimm R, Pich A, Eckerskorn C, Söhling B, et al. Substrate-specific selenoprotein B of glycine reductase from Eubacterium acidaminophilum . European Journal of Biochemistry. 1999;260 :38 - 17.
Behne D, Kyriakopoulos A, Meinhold H, Köhrle J. Identification of type I iodothyronine 5′-deiodinase as a selenoenzyme. Biochemical and Biophysical Research Communications. 1990; 173 :1143 - 18.
Arthur JR, Nicol F, Beckett GJ. Hepatic iodothyronine 5′-deiodinase. The role of selenium. Biochemical Journal. 1990; 272 :537 - 19.
Davey JC, Becker KB, Schneider MJ, Germain DL, Galton VA. Cloning of a cDNA for the type II Iodothyronine Deiodinase. The Journal of Biological Chemistry. 1995; 270 :26786 - 20.
Croteau W, Whittemore SK, Schneider MJ, Germain DL. Cloning and expression of a Cdna for a mammalian type III Iodothyronine Deiodinase. The Journal of Biological Chemistry. 1995; 270 :16569 - 21.
Lescure A, Gautheret D, Carbon P, Krol A. Novel selenoproteins identified in silico and in viva by using a conserved RNA structural motif. The Journal of Biological Chemistry. 1999; 274 :38147 - 22.
Tamura T, Stadtman TC. A new selenoprotein from human lung adenocarcinoma cells: Purification, properties, and thioredoxin reductase activity. Proceedings of the National Academy of Sciences of the United States of America. 1996; 93 :1006 - 23.
Lee SR, Kim JR, Kwon KS, Yoon HW, Leveine RL, Ginsburg A, et al. Molecular cloning and Charactrisation of a Mitochandrial Selenocysteine-containing Thioredoxin Reductase from rat liver. The Journal of Biological Chemistry. 1999; 274 :4722 - 24.
Mustacich D, Powis G. Thioredoxin reductase. The Biochemical Journal. 2000; 346 :1 - 25.
Watabe S, Makino Y, Ogawa K, Hiroi T, Yamamoto Y, Takahashi SY. Mitochondrial thioredoxin reductase in bovine adrenal cortex its purification, properties, nucleotide/amino acid sequences, and identification of selenocysteine. European Journal of Biochemistry. 1999; 264 :74 - 26.
Mills GC. Hemoglobin catabolism I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown. The Journal of Biological Chemistry. 1957; 229 :189 - 27.
Motsenbocker MA, Tappel AL. Effect of dietary selenium on plasma selenoprotein P, selenoprotein P1 and glutathione peroxidase in the rat. The Journal of Nutrition. 1984; 114 :279 - 28.
Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochimica et Biophysica Acta. 1982; 710 :197 - 29.
Takahashi K, Avissar N, Whittin J, Cohen H. Purification and characterization of human plasma glutathione peroxidase: A selenoglycoprotein distinct from the known cellular enzyme. Archives of Biochemistry and Biophysics. 1987; 256 :677 - 30.
Chu FF, Doroshow JH, Esworthy RS. Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. Journal of Biological Chemistry. 1993; 268 :2571 - 31.
Gromer S, Eubel JK, Lee BL, Jacob J. Human selenoproteins at a glance. Cellular and Molecular Life Sciences. 2005; 62 :2414 - 32.
Flohé L. Glutathione peroxidase brought into focus in into focus. In: Pryor WA, editor. Free Radicals in Biology. Vol. 5. New York: Academic Press; 1982. p. 223 - 33.
Maiorino M, Roveri A, Coassin M, Ursini F. Kinetic mechanism and substrate specificity of glutathione peroxidase activity of ebselen (PZ51). Biochemical Pharmacology. 1988; 37 :2267 - 34.
Epp O, Ladenstein R, Wendel A. The refined structure of the selenoenzyme Gultathione peroxidase at 0.2-nm resolution. European Journal of Biochemistry. 1983; 133 :51-69 - 35.
Nogueira CW, Rocha JBT. Organoselenium and organotellurium compounds: Toxicology and pharmacology. In: Rappoport Z, editor. The Chemistry of Organic Selenium and Tellurium Compounds. Vol. 1, 2, Part-II, Chapter 21. New York: Wiley; 2012 - 36.
Mukherjee AJ, Zade SS, Singh HB, Sunoj RB. Organoselenium chemistry: Role of intramolecular interactions. Chemical Reviews. 2010; 110 :4357 - 37.
Müller A, Cadenas E, Graf P, Sies H. A novel biologically active seleno-organic compound-1: Gultathione peroxidase-like activity in vitro and antioxidant capacity of PZ-51(Ebselen). Biochemical Pharmacology. 1984; 33 :3235 - 38.
Sies H, Matsumoto H. Ebselen as a glutathione peroxidase mimic and as a scavenger of peroxynitrite. Advances in Pharmacology. 1997; 38 :229-246 - 39.
Fong MC, Schiesser CH. Reactions of 2,2′-diselenobis(N-alkylbenzamides) with peroxides: A free-radical synthesis of Ebselen and related analogues. Tetrahedron Letters. 1995;36 :7329 - 40.
Mugesh G, Singh HB. Synthetic organoselenium compounds as antioxidants: Glutathione peroxidase activity. Chemical Society Reviews. 2000; 29 :347 - 41.
Mugesh G, Panda A, Singh HB, Punekar NS, R. J. Butcher gultathione peroxidase-like activity of diaryl diselenides-a mechanistic study. Journal of the American Chemical Society. 2001; 123 :839 - 42.
Bhabak KP, Mugesh G. Synthesis, characterization and antioxidant activity of some ebselen analogues. Chemistry—A European Journal. 2007; 13 :4594 - 43.
Bhabak KP, Mugesh G. Antioxidant activity of the anti-inflammantry compound ebselen; a reversible cyclisation pathway via selenenic and seleninic acid intermadates. Chemistry—A European Journal. 2008; 14 :8640 - 44.
Bhabak KP, Mugesh G. Amide-based glutathione peroxidase mimics: Effect of secondry and tertiary amid sustituenets on antioxidant activity. Chemistry, an Asian Journal. 2009; 4 :974 - 45.
Wirth T, Fragale G, Spichty M. Mechanistic course of the asymmetric Methoxyselenenylation reaction. Journal of the American Chemical Society. 1998; 120 :3376 - 46.
Back TG, Moussa Z. Remarkable activity of a novel cyclic seleninate ester as glutathione peroxidase mimetic and its facile in situ generation from allyl-3-hydroxypropyl selenide. Journal of the American Chemical Society. 2003; 125 :13455 - 47.
Back TG, Moussa Z, Parvez M. The exceptional glutathione peroxidase-like activity of Di(3-hydroxypropyl) Selenide and the unexpected role of a novel Spirodioxaselenanonane intermediate in the catalytic cycle. Angewandte Chemie, International Edition. 2004; 43 :1268 - 48.
Lesser R, Weiss R. Über Selenoxanthon und Selenoxanthon-carbonsäure. Über selenhaltige aromatische Verbindungen Über Ber. Dtsch. Chemische Berichte. 1914;47 :2510-2525 - 49.
Kapovits I, Kalman A. Formation and structure of a four-co-ordinate Organo-Sulphur (IV) compound. Chemical Communications. 1971; 12 :649-650 - 50.
Takaguchi Y, Furukawa N. First synthesis and structural determination of 1, 1′-spirobis(3H-2, 1-benzoxatellurole)-3, 3′-dione ([10-Te-4(C202)]). Heteroatom Chemistry. 1995; 6 :481-484 - 51.
Bhabak KP, Mugesh G. Functional mimics of glutathione peroxidase: Bioinspired synthetic antioxidants. Accounts of Chemical Research. 2010; 43 :1408-1419 - 52.
Zhang Z, Takahashi S, Saito S, Koizumi T. First synthesis and stereochemistry of enantiomerically pure spiroselenurane and spirotellurane using the 2-exo-hydroxy-10-bornyl group as a chiral ligand. Tetrahedron: Asymmetry. 1998; 9 :3303-3317 - 53.
Zhang J, Saito S, Koizumi T. Acidic and basic hydrolysis of an optically pure Spiro- λ 4-sulfurane: Completely opposite Stereochemical outcome. Journal of the American Chemical Society. 1998;120 :1631-1632 - 54.
Kapovits I, Rabai J, Szabó D, Czako K, Kucsman A, Argay G, et al. Diaryldiacyloxyspirosulfuranes. Part 3. Sulfuranes with five-, six- and Sevenmembered Spirorings: Syntheses and molecular structures. Journal of Chemical Society, Perkin Transactions. 1993; 2 :847-853 - 55.
Selvakumar K, Singh HB, Goel N, Singh UP, Butcher RJ. Synthesis and structural characterization of pincer type bicyclic diacyloxy- and diazaselenuranes. Dalton Transactions. 2011; 40 :9858-9867 - 56.
Jacob C, Giles GI, Giles NM, Sies H. Sulfur and selenium: The role of oxidation state in protein structure and function. Angewandte Chemie, International Edition. 2003; 42 :4742-4758 - 57.
Back TG, Kuzma D, Parvez M. Aromatic derivatives and tellurium analogues of cyclic Seleninate esters and spirodioxyselenuranes that act as glutathione peroxidase Mimetics. The Journal of Organic Chemistry. 2005; 70 :9230-9236 - 58.
Sarma BK, Manna D, Minoura M, Mugesh G. Synthesis, structure, Spirocyclization mechanism, and glutathione peroxidase-like antioxidant activity of stable spirodiazaselenurane and spirodiazatellurane. Journal of the American Chemical Society. 2010; 132 :5364-5374 - 59.
Lamani DS, Bhowmick D, Mugesh G. Substituent effects on the stability and antioxidant activity of spirodiazaselenuranes. Molecules. 2015; 20 :12959-12978 - 60.
Lamani DS, Bhowmick D, Mugesh G. Spirodiazaselenuranes: Synthesis, structure and antioxidant activity. Organic & Biomolecular Chemistry. 2012; 10 :7933-7943