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Selenium Containing Compounds from Poison to Drug Candidates: A Review on the GPx-like Activity Claudio Santi*,1, Caterina Tidei1 , Claudia Scalera1 , Marta Piroddi2 and Francesco Galli2 1

Dipartimento di Chimica e Tecnologia del Farmaco, Via del Liceo 1- 06136 Perugia Italy; 2Dipartimento di Medicina Interna, Via del Giochetto 06126 Perugia Italy Abstract: Oxidative stress results from the formation of reactive oxygen species (ROS) such as peroxides that cause damage to cell membranes and react with various biomolecules in mammalian cells. The selenoenzyme glutathione peroxidase (GPx) destroys peroxides by catalyzing their reduction to alcohols or water with the stoichiometric reductant glutathione. The effects of oxidative stress have been implicated in a variety of degenerative processes and disease states and for these reasons, there is considerable interest in the discovery of small molecule compounds that could reproduce a GPx-like activity. A review on the most recent acquisition in this area is here reported.

Keywords: Selenium, selenoprots, glutathione, ROS, ebselen. INTRODUCTION For a long time selenium has been considered a poison. The first observation about the toxicity of this element dates back to 1285 when Marco Polo lost his horses crossing the Shanxi Province of Western China; this event was explained only after the discovery of selenium in 1817 by the Swedish chemist Jöns Jacob Berzelius and it was ascribed to the high concentration of this element in forages growing in the region that caused selenosis in livestock. Later, several studies confirmed the occurring of important disorders in animals [1, 2] and humans [3] due to selenium bioaccumulation and thereby a role in the genesis of cancer was postulated [4]. In th the second half of the 20 century, selenium began to be attractive for its chemical and biochemical properties. In 1957, Schwarz and Foltz discovered that it is an essential nutritional trace element, able to prevent necrotic liver degeneration in animals [5]. From 70’s, many human diseases were correlated to selenium deficiency such as Keshan and Kashin-Beck disease [6, 7], a cardiomyopathy and an osteoarthropathy endemic in some areas of China. Also some others disorders such as neurodegeneration, altered immune responses, cardiovascular diseases and cancers can be correlated to insufficient selenium levels into the body [8-10]. The physiological role of selenium began to be explained when it was recognized to be a part of the bacterial formate dehydrogenase [11] and glycine reductase [12] and of some mammalian protein, such as the glutathione peroxidase (GPx) [13]. These are all members of a large family of selenoproteins, present in archea, bacteria and eukaryotes, and involved in important biological functions such as regulation of redox signaling, antioxidant activity, synthesis and metabolism of the thyroid hormone. Selenium plays a key role *Address correspondence to this author at the Dipartimento di Chimica e Tecnologia del Farmaco, Via del Liceo 1- 06136 Perugia Italy; Tel: +39 075 5855102; Fax: +39 075 5855116; E-mail: [email protected] 1872-3136/13 $58.00+.00

in the catalytic activity of these enzymes and is present in the form of selenocysteine (Sec), which is considered as the 21st amino acid and owns peculiar features concerning its biosynthesis and incorporation into proteins. Firstly, Sec does not exist in cells as a free amino acid but it is synthetized in the growing polypeptide starting from a serine residue: the formation of a unique seryl-tRNASer occurs and is followed by the conversion into a unique selenocysteyl-tRNASec using a selenophosphate [14] as selenium source. Secondly, Sec is encoded by a UGA codon that is commonly considered a stop codon but, in this case, contains the information for Secinsertion [15]; the reinterpretation of this genetic information is due to a particular secondary mRNA structure, called SECIS element (SElenoCysteine Insertation Sequence) [16], and to the recruitment of many protein factors. The insertion of Sec in proteins is a complex and energetically expensive process for the cells. Nevertheless, it has never been substituted during the evolution by the simpler use of a cysteine and this can be a consequence of the advantages of chemical and physical properties of selenium compared to those of sulphur. First of all, the lowest pKa of selenolate (≈5.2) compared with that of thiolate (≈8.5) influences the protonation at physiological pH (≈7.4); cysteine exists mainly in the protonated form while Sec is dissociated conferring higher nucleofilicity to the selenium atom. The selenol/diselenide exchange reactions, observed by NMR spectroscopy, proceed at a rate 107 times greater than the thiol/disulfide exchange reactions [17]. On the basis of these considerations, selenoproteins result to be better in the interactions with electrophilic species, in the context of redox signaling pathways as well as in the catalytic cycles of glutathione peroxidase. GPx is the first selenoprotein discovered in mammals and one of the most studied because of its central role in the defense against the oxidative stress. It is usually imposed on © 2013 Bentham Science Publishers

26 Current Chemical Biology, 2013, Vol. 7, No. 1

cells as a result of one of the three factors: 1) an increase in oxidant generation, 2) a decrease in antioxidant protection or 3) a failure in repairing oxidative damage. Cell damage is induced by reactive oxygen species (ROS) that can be either free radicals or reactive anions containing oxygen atoms or oxygen containing molecules that can either produce free radicals or that are chemically activated by them. The main source of ROS in vivo is aerobic respiration and the main damage to cells results in the alteration of some macromolecules such as polyunsaturated fat acids in membrane lipids, proteins and DNA. Eight different GPx have been identified: three isoforms are not actually selenoproteins because Sec has been replaced by a Cys residue and as expected, they are characterized by less efficiency in the catalytic activity [18]. The most important GPx, the GPx1 or cytosolic GPx, GPx2 or gastrointestinal GPx, GPx3 or extracellular GPx, GPx4 or phospholipid peroxide GPx and the recently discovered GPx6, have different physiological localization and substrate specificity but are all selenium containing enzymes and reasonably they have the same catalytic mechanism. Selenium atom in Sec is stabilized as selenolate by the formation of hydrogen bonds with a tryptophan and a glutamine residues generating, in the active site of the enzyme, a “catalytic triad” Fig. (1) [19].

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balancing the ROS production, several research groups are nowadays interested in the synthesis of small organoselenium compounds able to reproduce the antioxidant activity of glutathione peroxidase. GPx

O

H N

H N

N H SeH

GR

GPx O

H N

N H SeSG

GSH

H2O

3 NADP+

Scheme 1. Catalytic reduction of peroxides by Glutathione Peroxidase.

EXPERIMENTAL ACTIVITY

EVALUATION

OF

GPx-LIKE

In literature, several methods for the evaluation of GPxlike activity have been reported: Wilson et al. [24] developed a procedure based on spectrophotometrical measurement at 366 nm of the NADPH concentration when it was used as a cofactor by the glutathione reductase for the reduction of GSSG to GSH (Scheme 2):

GSSG + NADPH + H+

GPx GSH reductase

GSSG + 2 H 2O 2GSH + NADP+

NADP + + 2H 2O

NADPH + H + + H2O 2

In this form (1), Sec is able to reduce hydrogen peroxide as well as organic peroxides affording water or the corresponding alcohols, respectively, in association with the unstable selenenic acid (2) that reacts with a molecule of reduced glutathione (GSH) to generate a selenenyl sulfide intermediate (3). A second GSH molecule attacks the Se-S bond regenerating the selenol group and producing a molecule of oxidized glutathione (GS-SG) that is enzymatically reduced back to GSH by the glutathione reductase (GR)NADPH system. (Scheme 1)

N H SeOH

GSH

GSSG

NADPH

O

2

1

2GSH + H 2O 2

Fig. (1). Catalytic Triad” of Glutathione Peroxidase.

ROH

ROOH GPx

Scheme 2. NADPH as probe of GPx-like activity at 366 nm.

Another method based on UV spectroscopy uses the thiobenzene (PhSH) to evaluate the reduction of H2O2 by measuring the concentration of the produced disulfide PhSSPh at 305 nm [25] (Scheme 3). 2PhSH + H2O 2

cat

PhSSPh + 2 H 2O

Scheme 3. PhSSPh as probe of GPx-like activity at 305 nm.

It is known that GPx and its sulfur mutant are overoxidated to seleninic acid (enz-SeO2H) and sulfinic acid (enzSO2H) respectively upon storage [20, 21] but only the selenium derivative can be reduced to the corresponding selenol (enz-SeH) by treatment with an excess of glutathione [20].

Some NMR based methods have also been reported. All these assays consist of the measurement of the time required to reduce a thiol concentration of 50% in the presence of a stoichiometric amount of H2O2 and a catalyst.

Considering that a number of human diseases such as cancer, neurodegeneration, inflammation, immune disorder, atherosclerosis, cystic fibrosis [22, 23] have been correlated to the reduced ability of the radical scavenging systems on

Engman et al. [26] used different thiols (Nacetylcysteine, tert-buthyl mercaptan and 1-octyl mercaptan) because of their slow oxidation rate. Iwaoka et al. reported a similar test using a dithiol, the dithiotreitol (DTT) and methanol-d6 as solvent [27] Fig. (2).

Selenium Containing Compounds from Poison to Drug Candidates

HO HO

HO HO

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and its derivatives can be associated with the ability to mimic the enzymatic properties of GPx, its catalytic cycle has been for a long time not clear and a controversial topic. This is probably due to the use of different thiols and peroxides used for the GPx-like activity. In the first proposed mechanism the ebselen 4 reacts with GSH to produce the selenenyl sulphide 5 as precursor of the active species 6 which derives from a further reaction with a molecule of GSH. The selenol 6 reduces the peroxide to give the selenenic acid 7 that can be reduced back to 5 by the reaction with a second equivalent of thiol (Scheme 5) [37].

S S

O

H2O

SH SH

GSH

N Ph Se 4 O

O

Finally, Back and Dyck [29] monitored the oxidation of benzylthiol (BnSH) in the presence of tert-butyl hydroperoxide (TBHP) and 10% of catalyst determining the concentration of dibenzyl disulfide (BnSSBn). BnSH + t-BuOOH

catalyst 10%

BnSSBn + t-BuOH

Scheme 4. Oxidation of BnSH by TBHP.

Using Benzylthiol as surrogate for glutathione, the oxidation reaction to be conveniently monitored by HPLC or NMR methods, thanks to the presence of a chromophore and of the characteristic benzylic proton resonance, respectively.

Se 5 SG

7 O

H2O

N Ph H SeH

H2O2

GSH GSSG

6 Scheme 5. Catalytic mechanism of ebselen, first hypothesis.

Using as cofactors, aryl thiols such as PhSH or BnSH ebselen showed to be a poor catalyst on reducing peroxides [37] and Mugesh demonstrated that it is due to a thiol exchange reaction that takes place at the selenenyl sulphide 5 [37,38,39]. (Scheme 6) A strong Se—O interaction increases the electrophilicity of the selenium center disfavoring the attack of the thiol to the sulphur atom and consequently the formation of the active species 6.

EBSELEN AND EBSELEN ANALOGUES Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)one) (4) is one of the most promising synthetic GPx-mimics [30] and it was the first to be used in clinical trials as an antioxidant and neuroprotective agent [31]. It is a non-toxic molecule because its cyclic selenamidic structure provides a high stability and prevents the release of elemental selenium. Ebselen is an excellent ROS scavenger and the rate of the reaction between 4 and peroxynitrile is about three orders of magnitude higher than that of naturally occurring small molecules such as ascorbate, cysteine and methionine [32]. The pharmacological activity of Ebselen cannot be ascribed only to its scavenging properties because it is also responsible for the inhibition of several enzymes involved in inflammatory responses, such as nitric oxide synthase (NOS) [33], lipoxygenase (LOX) [34], cycloxygenase (COX) [35], protein kinase (PKC), NADPH oxidase [36]. The sulfur analog, PZ25, has shown to have no GPx-like activity [31], confirming the crucial role of the selenium atom for the catalytic activity. Even if most of the biological activities of ebselen

N Ph H

N Ph H SeOH

Fig. (2). T50 for the oxidation of DTT. We recently modified this procedure using as solvent D2O in order to obtain experimental conditions closer to the physiological one. In this solvent the oxidation is very fast and an automatic routine was optimized to acquire an 1HNMR spectrum every 16 seconds [28].

H2O

GSH

HN

Ph O

HN B

SeH

A

O Se 5 S Ph

6

Ph

5

A B

SH

A = Thiol exchange B = Thiolysis

Scheme 6. Thiolysis vs thiol exchange.

Extensive investigations demonstrated that 4 reacts with hydrogen peroxide in the absence of thiol producing the corresponding seleninic acid 8 that, by reaction with 2 equivalents of thiol, leads to the selenenic acid 7 and, subsequently, the selenenyl sulphide 5. In the absence of thiol, compound 7 eliminates a molecule of water regenerating the ebselen 4. (Scheme 7)


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The rate-limiting step is the disproportionation of 5 to diselenide 9 and it depends on the nature of thiol employed and GSH showed higher reactivity than PhSH. Theoretical calculations confirmed that thiol’s reduction to selenenylsulfide 5 is favored over oxidation of Ebselen to the corresponding selenoxide under extremely oxidizing conditions. Furthermore, selenol/diselenide regeneration (5  9) depend upon the nature of the thiol reductant. In the case of GSH, this reaction is accelerated by the intramolecular interaction S-O [40]. O

H2O

compared to 15) and this effect is higher when the substituent is an electron withdrawing group that contributes on reducing the nucleophilicity of the nitrogen atom [47]. O

O N Ph

Se O

N

Se

O

HN R

10

R

PhSH

N 13

R

N Ph H Se OH 8 O

Se

NO2

N Ph H Se 5 SPh

N Se

N Et Se

N Se

O

O

20

19

18

PhSH

NH

16 R = H 17 R = OMe

14 R = NO2 15 R = H

O

O

PhSSPh

O

NH Se

H2O2

Se 7 OH

Se

O 11 R = iPr 12 R = Ph

4

N Ph H

OH

N

PhSH

N Ph Se

O

O N Ph

H2O

Scheme 8. Ebselen analogues.

O

H2O

PhSH

N Ph H H2O2

Se 9

2

PhSSPh

Scheme 7. Catalytic mechanism of ebselen.

Several analogs of Ebselen have been developed in order to enhance the GPx activity. (Scheme 8) This purpose has been achieved by introducing substituents, such as a nitro group, in ortho position (10) [41]: besides an electronic effect, it plays an important steric influence because the hindrance at selenium center prevents thiol exchange reactions allowing the formation of selenol, that is the actual catalytically active species [42]. It was recently reported that the GPx-like activity of 10, 11 and 13 is nine, three and two times, respectively, greater than that of ebselen. All these compounds are stabilized by an intramolecular coordination (with a nitro-, amide- or oxazoline substituent in 6-position)[43] and computational analysis confirmed that these groups are also responsible for a sterical protection of the selenium by the attack of the sulfur [44]. Surprisingly, in the case of the benzamido derivative 12, the activity resulted to be reduced compared to that of the ebselen but this was correlated to the low solubility of this molecule in the buffer used for the analysis [45]. Passing from the cyclic selenamides moiety of 4 to the benzoselenazol derivatives 14 and 15, the antioxidant activity is considerably lost but it can be partially recovered when the selenium containing heterocycle is a benzoselenazine 16 and 17 [46]. The introduction of a substituent on the nitrogen atom produces a negative effect on the GPx like activity (e.g. 18

On the contrary, Mugesh and Bhabak demonstrated that starting from benzo[d][1,2]selenazol-3(2H)-one 21, the introduction of a variously substituted aromatic ring bonded to the nitrogen atom enhances the activity (22, 23 and 24). They demonstrated that similar results can be also obtained with non aromatic substituents such as an hydroxyethylenic chain (25) or electron withdrawing groups such as a thioacetamidic unit (26) [48]. O

O

NH Se

N Se

O OH

N Se

22

21

O Br

N Se

OH

25

24

O S

26

23

O

N Se

N Se

OH

OH

Se NAc

NH2 27

Scheme 9. Benzo[d][1,2]selenazol-3(2H)-one derivatives.

Back et al. synthetized the camphor based selenamide 27 that, tested with BnSH/TBHP system, produced a t/2 of 18 h compared to 42 h for ebselen. The authors demonstrated a mechanism similar to that firstly proposed for Ebselen (Scheme 5) that involves 27 as procatalyst. It reacted with thiol generating the selenenyl sulphide 28 and then the sele-



nol 29 that is responsible for the peroxide reduction [49]. (Scheme 10) OH

OH

Se

BnSH

NAc

BnSH

NHAc

BnSSBn

28

H2O

27

S Bn

Se

OH OH

BnSH

SeOH NHAc

30

SeH NHAc

29

Similarly, the presence of a nitrogen in the ortho position respect to the selenium produces a positive effect on diselenides 42 and 43 but resulted to be non-relevant for the activity of the corresponding diaryl selenides 44 and 45 [24]. Structurally correlated diselenides were prepared (46-52). It is interesting to observe that the introduction of a methoxy group at the 6-position of the aromatic ring produces a significant enhancement of the catalytic activity with respect to the parent compounds. This effect has been ascribed to the fact that the methoxy group blocks the attack of the thiol to the selenium directing the nucleophile toward the sulfur center of the selenenyl sulfide intermediate and thus regenerating the selenol that is the actual catalyst [52].

tBuOOH tBuOH

OR'

Scheme 10. Catalytic cycle for 27.

Se)2

Se) 2

Benzoselenazolyl nucleus (31-33, scheme 11) were prepared by Galet. In these structures the selenium is not directly bonded to nitrogen atom and its electrophilicity resulted to be strongly reduced. As a direct consequence of that, compounds 31-33 are not able to react with the thiol and they have no antioxidant activity. [50] H N

R' N O

R 31

R

34 OH

32

Se 33

41 N

N

Se) 2

Se) 2

42

43

Se

Se

DISELENIDES AND SELENOLATES

In 1998, Wirth reported a series of diselenides containing an oxygen as heteroatom in close proximity to selenium. For these compounds, the GPx like activity and the pro-oxidant properties were studied using NADPH based assay. Diselenides 35-41 depicted in Scheme 12 showed antioxidant activities. The steric hindrance and the presence of an electron withdrawing substituent in the aromatic ring (36, 38 and 39, respectively) resulted to be detrimental for the GPx like activity that seems to be directly correlated to the electron density at the selenium atom. Similar negative effects can be observed when the hydroxyl group, present on the side chain, is substituted by a methoxy group (37) or it is in a remote position no more suitable for the nonbonding interaction with the selenium (40). The best result in this series of compounds was observed for diselenides 41 [51].

N

N

Scheme 11. Benzoselenazolyl derivatives.

The evidence that a diselenide (9) should be a key intermediate in the catalytic mechanism of the ebselen induced several research groups to take in consideration this class of compounds as Gpx mimics. Wilson et al. first discovered that diphenyl diselenide 34 is two times more active compared to ebselen and they concluded that the selenium nitrogen bond is not necessary for the Gpx activity [24]. Furthermore, they reported that an heteroatom in a suitable position to establish with the selenium a nonbonding interaction can take part in the catalytic mechanism promoting the oxidative cleavage of Se-Se bond and stabilizing the selenol, mimicking the catalytic triad of the enzyme.

MeO Se) 2

40

O

Se

35 R = H, R' = H 36 R = Me, R' = H 37 R = H, R' = Me 38 R =CH(OH)Et, R' = H 39 R = CF3, R' = H

Se) 2

H N O

HO

Se O

29

N

N

44

N R Se) 2

R

45

46 R = Et 47 R = nPr 48 R = iPr

N R Se) 2

49 R = Me

R

50 R = Et 51 R = nPr 52 R = iPr

OMe

O N N

Fe

Se)2 53

Se) 2

54

Scheme 12. Diselenides.

It was reported that the N,N-dimethylaminoferrocene 54 catalyzes the reduction of H2O2 in the presence of a thiol more efficiently than ebselen (4), axazoline based diselenide 53 and dialkyl based diselenides 46-48. Singh et al. demonstrated that the peroxidase-like activity of these compounds depends on the strength of Se—N nonbonded interactions in the intermediates involved in the catalytic process. In 54, the basic nitrogen produces a stabilizing interaction in selenol and selenenic acid derivatives, whereas in the less active compounds the nitrogen interacts with selenium in all three


Santi et al.

intermediates (selenol and selenenic acid and selenenyl sulfide). From spectroscopic and crystallographic evidences, it was demonstrated that for a good GPx-like activity, the nitrogen must abstract a proton from the selenol activating it into the corresponding selenolate anion and interacting strongly with the selenium of the selenenic acid intermediates, increasing the stability of this species against further oxidation and increasing the electrophilicity of the selenium that suffers from the nucleophilic attack of the thiol. Furthermore, the basic nitrogen contributes to deprotonate the sulfydryl group to provide a high local concentration of nucleophilic thiolate anion. Generalizing these concepts: diselenides having strong Se-N interaction are inactive due to the ability of their corresponding selenenyl sulfide to enhance the reverse GPx cycle. On the other hand, the diselenides having weak Se-N interactions are found to be more active due to the fast reaction of the selenenylsulfide with thiol forming the corresponding disulfide and the active selenol [53]. (Scheme 13) H2O2

N

PhSSPh

weak Se-N

H Se

H2 O

H2O2

N

PhSH

N

Se-N strong

Diaryl diselenide containing an alanine as ortho donating group was already known as inhibitor of the nitric oxide synthase and as cytokine inducer activity. In a recent study, on its GPx-like activity, it showed a catalytic performance only slightly better than ebselen and it was interesting to observe that the chirality of the alanine does not play any significant role in altering the efficiency. Similar results were obtained using both L-alanine and D-alanine [56].

Se

Se

MeO

Se PhS

Se)2

The introduction of a methoxy substituent ortho to the selenium (64-66) makes the basicity of the amino group perfect for the catalysis, preventing the direct interaction between selenium and nitrogen in the selenols and increasing their zwitterionic characters. Furthermore, the presence of 6OMe group contributes with steric and electronic effects to protect selenium from the overoxidation to seleninic and selenonic acid increasing its electrophilicity in the sulfide intermediate and preventing the undesirable thiol exchange [55].

The conformationally restricted peri diselenide 67 showed a remarkable catalytic activity and it was demonstrated that it was increased by the presence of the electrondonating methoxy substituents that facilitate the ratedetermining Se(II) to Se(IV) oxidation step in the catalytic cycle. Better results can be obtained with the corresponding tellurium derivatives [57].

Se HO

N

PhSH

can be correlated to a weaker Se - heteroatom interaction. (Scheme 14)

OMe

PhSH H2O

67

Scheme 13. Role of the Selenium-Nitrogen nonbonding interaction. Scheme 15. Conformationally restricted peri diselenide 67.

Recently, some theoretical investigations demonstrated the effect of Se-O(N) interactions on the GPx like mechanism [54]. Sec- and tert-amide based diselenides (55-59 and 60-63, respectively) resulted to be inactive towards the PhSH and therefore the catalytic GPx-like activity should be ascribed completely to their direct reaction with H2O2. O N H Se)2

O R

N R Se)2 H

55 56 57 58 59

R= H R = Me R = Et R = nPr R = iPr

60 R = Me 61 R = Et 62 R = nPr 63 R = iPr

O R

N R Se)2

R

OMe 64 R = Me 65 R = Et 66 R = nPr

Scheme 14. Amide based diselenides.

Tertiary amides 60-63 showed higher GPx activity compared to the secondary one (55-59) and also in this case, it

Starting from the consideration that selenols 68 and 69 (Scheme 16) are activated by nearby heteroatoms in the form of selenolate anion [19], very recently, we prepared a new interesting class of bench stable selenolates (70-71) in which selenium is stably bonded to a zinc atom. The PhSeZnchloride 70 showed a really interesting reactivity in aqueous medium and for this reason was evaluated as potential GPxmimics [58]. The synthesis of 70 and 71 can be easily achieved by oxidative insertion of the elemental metal starting from the commercially available PhSeCl and PhSeBr, respectively [59]. It is worth mentioning that similar reactions effected starting from selenenyl halides containing ortho donating heteroatoms failed and this should be correlated to the coordinating effect of the heteroatom to the selenium atom that occurs faster and results to be stronger than the coordination with the zinc atom. Considering that the oxidation state of selenium in PhSeZnCl is the same as in the catalytic site of the enzyme, the reactivity towards thiols in the presence of air and peroxides as stoichiometric oxidants was evaluated and correlated to the putative antioxidant activity [28].



It was demonstrated that a stoichiometric amount of 70 promotes the quantitative oxidation of glutathione by air in 24 h and it was confirmed that, in the same conditions and without catalyst, the spontaneous oxidation process is absent. When the oxidant is hydrogen peroxide, the self-oxidation of GSH was obviously faster (10h) but we demonstrated that it was considerably accelerated by 70 (5h), demonstrating its remarkable GPx-like activity.

The oxidation of selenomethionine has been investigated by 77Se-NMR and theoretical calculations and the formation of a cyclic selenurane was demonstrated in addition to the expected selenoxide [61]. H2O2

NH2

H2O

Se)2

HOOC

NH2 SeO2H

HOOC 75

74

H2O

O

R

H N Ph Se H 68

O

! Se

H N Me Se H

H2O2

70 X = Cl 71 X = Br

69

NH2

H2O

ZnX !

GSH

SeOH

HOOC

termodynamically not feasible

76

NH2 SeH

77

SELENIDES AND SELENOXIDES

Scheme 16. Selenolates.

PhSeZnCl 70

H2O

H2O2 H2O

Zn(OH)Cl

PhSe O ZnCl 72 +H 2O

-H2O

PhSeOH

Zn(OH)Cl G-SH

G-SS-G G-SH

GSH

Scheme 18. Catalytic cycle of Selenocystine.

Se Cl

PhSeH

SeSG

HOOC

GSSG

Zn

GSSG H2O

NH2 HOOC

GSH

H2O2

78

Me N Me

31

PhSeSG ZnCl 73

H2O

Scheme 17. Catalytic cycle for PhSeZnCl.

The GPx-like activity of 70 evaluated by NMR was higher compared to those of other selenium containing compounds. The T50 was 1.5 times shorter with respect to that of diphenyl diselenide and this suggests that PhSeZnCl does not simply act as a precursor of the selenenic acid intermediate, which is the case of diphenyl diselenide. Reasonably, a zinc containing Lewis acid plays an active role in the catalytic cycle as reported in Scheme 17 [28]. Iwaoka extensively studied the catalytic cycle of the Selenocystine, the dimeric form of the corresponding natural selenium containing amino acid. He demonstrated that the GPx-like activity of this diselenide is initiated by the reaction with hydroperoxide to form CysOH and CysO2-, rather than by the reaction with thiol to form CysSe-. CysSeOH and CySeO2- subsequently are reduced by thiol producing CysSeSG, that is the precursor of the active selenolate CysSe- [60]. (Scheme 18)

A series of ω-hydroxyalkyl selenides were studied by Back and co-workers [62]. The oxidation of compounds such as 79 produced the corresponding selenoxide that affords the cyclic selenolate 80 through a [2,3]-sigmatropic rearrangement in the presence of an excess of oxidant. This latter showed a remarkable catalytic activity, 17 times higher than ebselen, suggesting that less studied S-O interaction/bond can also act as high effective GPx mimetics [63]. During the synthesis of different hydroxyalkyl derivatives, the same authors obtained the spirodioxyselenurane 82 and demonstrated for this compound a catalytic activity comparable to 80 [64]. It is interesting to note that the activity of selenide 81 is correlated to its transformation into 82 through the formation of a selenoxide intermediate. Benzofused ring systems 83-85 showed a catalytic activity greatly diminished, compared to that of their aliphatic analogs on the reduction of TBHP [60]. More recently, Mugesh reported that the structurally similar spirodiazaselenurane 86 exhibits a GPx-like activity similar to that of Ebselen. He also demonstrated that the substitution of the selenium with tellurium produces a remarkably enhancement of the catalytic activity consistent with the involvement of a more efficient redox cycle between telluride and telluroxide [65]. Water soluble cyclic selenide 88 showed higher GPx-like activity than linear analog 87 and it was correlated to the evidence that the cyclic structure elevates the HOMO energy level making the selenium more susceptible to the surroundings. Very recently, we reported that also some vinyl selenides (89, 90) can act as catalyst in the oxidation of peroxides and 77Se-NMR evidences indicated that the catalytic cycle starts with the oxidation of the selenium into the corresponding selenoxide [28]. In an attendant publication, Braga described kinetic results indicating that the GPx-like catalytic activity of organoselenides does not follow a Se(II) Se(IV) redox cycle. In the presence of hydrogen peroxide, selenoxides 91 are con-


Santi et al.

verted to hydroxy perhydroxy selenanes 92 which are better oxidizing agents than selenoxides [66]. (Scheme 20) O Se

Se

Se O

O Se O

OH

HO

OH 79

81

80

O Se

O Se

84

83

82

O Se O

O

O

O 85

O N Se N

Se HO

O

Se OH

OH

HO

Liu and coworkers first reported a small molecular micellar nanoenzyme model which employs benzenseleninic acid (PhSeO2H) as a catalytic center and the cationic hexadecyltrimethylammonium bromide as surfactant [69]. Fig (3) It showed substrate specificity for both 3-carboxy-4nitrobenzenthiol and cumene hydroperoxide and the catalytic reaction rate resulted to be 500 times higher compared with that of PhSeO2H alone. Similarly, a block copolymer micelles of polystyrene-block-poly(acrylic acid) was used as matrices for the incorporation of the water-insoluble dibenzyl diselenide which showed GPx-like activity in aqueous solution only after the inclusion into the micelles [70].

88

87

86

supramolecular chemistry shifts the research focus on developing functional systems, such as supramolecular enzyme models. These structures can be readily constructed by self assembly which resulted to be an efficient strategy for generating highly ordered systems to mimic the biopolymers [68].

O Ph

Ph

SePh

SePh

90

89

Scheme 19. Selenides. H2O2 R1 Se R2

Fig. (3). Micellar enzyme model with a catalytic selenium center.

OH O H+ R1 Se R2 R1 Se R2 91 H2O H2O

OOH R1 Se R2 OH 92

H2O2

OH R1 Se R2 OH GSSG

GSH

Scheme 20. Oxidation mechanism of selenides.

A selenoxide intermediate was proved to be responsible also for the antioxidant activity observed for three unusual stable selenium cations (93, 94, 95) and the mechanism was investigated by density functional theory calculations [67]. (Scheme 21) N-p -RC6H4 Se O

N

O

X

93 X = Cl, R = Cl 94 X = Br, R = Br 95 X = Br 3, R = H

Scheme 21. Stabilized cations.

ARTIFICIAL SELENOENZYMES Three important factors contribute to maintaining efficient GPx catalytic activity in the enzyme: - a selenium center, - the recognition site, - the hydrophobic cavity. Recently,

Nanosized particulate glutathione peroxidase mimic has been recently reported [71]. The catalytic selenocysteine was conjugated to a hydrophilic linear polysaccharide and this conjugate can spontaneously form the self-aggregated particle with diameters of several hundred nanometers. The nanosized aggregates showed a catalytic activity 20-times higher than that of the free Sec and this was ascribed to: (i) the improvement of the water solubility and stability of the selenium compound, (ii) the capability to form an hydrophobic environment around the selenium center, (iii) the concentration of the local selenium compounds in the selfaggregated particle. Cyclodextrin based selenonic acid and guanidinefunctionalyzed β-cyclodextrin were combined as the catalytic and the binding site respectively in a novel giant nanotube model of artificial selenoenzyme [72]. Fig. (4). Both the functional groups are orderly positioned on the surface of the nanotube in a suitable location to contribute to the high GPx catalytic activity conferring new easily accessible material potential applications in designing biosensor and bio-medicals. Apart from cyclodextrins, dendrimers and hyperbranched polymers with the three-dimentional topology structures represent a sort of host molecules that can lodge a large range of hydrophobic guest molecules. Introducing selenium (or tellurium) into the core of dendrimers some artificial GPxs was successfully achieved, a selected example relative to a Frèchet-type poly(aryl ether) dendrimer equipped with a catalytic diselenide core is reported in Fig. (5) [73].



33

Fig. (4). Nanotube selenoenzyme model. MeOOC

MeOOC

O

COOMe

O

O

COOMe

O O

O

O

O O

O

MeOOC

COOMe O

O

Se

MeOOC O

MeOOC

O

O

O

O

Se

COOMe

O

O

O

O O

O

COOM e

O

O

O

MeOOC

COOMe MeOOC

O

O COOMe

COOMe

COOMe

Fig. (5). Dendrimer for artificial selenoenzymes.

Finally, Sec containing artificial polypeptides with a GPx-like activity were recently synthesized using a selective introduction of a Sec moiety under physiological conditions [74]. The insertion into selenoproteins occurs by a specific translational control process and it is quite difficult to express the Sec containing polypeptides even with the modern genetic engineering techniques. CONCLUSION

conditions more similar to the physiological one and in order to better define the mechanism involved in the selenium mediated reduction of peroxides in the living systems. Starting from Ebselen, several new classes of selenium derivatives are now under investigation and the development of new and efficient strategies to afford selenides and diselenides represents an interesting opportunity for the potential use of these compounds as antioxidant but also as new green bio-mimetic catalysts [75, 76].

In this review we underlined the wide and growing interest on preparing new small selenium containing molecules able to act as glutathione peroxidase mimics. This interest is strongly correlated to the high potential therapeutic application of drugs that can finely modulate a catalytic redox equilibrium involved in several different pathologies.

ABBREVIATIONS

Nevertheless, by the state of the art, the development of new cell free tests for the evaluation and the comparison of the catalytic activity between different selenium containing compounds remains an important feature, in order to find

BnSH

= Benzyl Thiol

BnSSBn

= Benzyl Disulfide

COX

= Cycloxygenase

Cys

= Cysteine

DTT

= Dithiotereitol

GPx

= Glutathione Peroxidase


(GR)-NADPH

= Glutathione Reductase NADPH dependent

GSH

= Glutathione

GSSG

= Glutathionil Disulfide

HOMO

= High Occupied Molecular Orbital

LOX

= Lipoxygenase

NADPH

= Nicotinamide Adenine Dinucleotide Phosphate

NOS

= Nitric Oxide Synthase

PhSH

= Benzothiol

PhSSPh

= Diphenyl Disulfide

PKC

= Protein Kinase

ROS

= Reactive Oxygen Species

Sec

= Selenocysteine

SECIS

= SElenoCysteine Insertion Sequence

TBHP

= t-Buthylhydroperoxide

CONFLICT OF INTEREST

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The authors confirm that this article content has no conflicts of interest. [20]

ACKNOWLEDGEMENTS This work was performed with the financial support from Fondazione Cassa di Risparmio di Perugia, Ricerca di Base 2010 – progetto 2010.011.0415, M.I.U.R. (Ministero Italiano Università e Ricerca) Awarded to CS* and FG and Regione Umbria (POR UMBRIA FSE 2007-2013) awarded to CS. The authors also thank the National Projects PRIN2007 (Progetto di Ricerca d’Interesse Nazionale) and the Consorzio CINMPIS, Bari (Consorzio Interuniversitario Nazionale di Metodologie e Processi Innovativi di Sintesi).

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Received: January 01, 2012

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Revised: March 15, 2012

Accepted: April 01, 2012