Synthesis of enantiomerically pure glycerol derivatives containing an organochalcogen unit: In vitro and in vivo antioxidant activity

Patrick C. Nobre; Henrique A. Vargas; Caroline G. Jacoby; Paulo H. Schneider; Angela M. Casaril; Lucielli Savegnago; Ricardo F. Schumacher; Eder J. Lenardão; Daiana S. Ávila; Luiz B.L. Rodrigues Junior; Gelson Perin

doi:10.1016/j.arabjc.2017.08.007

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Original article

13 (

); 883-899

doi:

10.1016/j.arabjc.2017.08.007

Synthesis of enantiomerically pure glycerol derivatives containing an organochalcogen unit: In vitro and in vivo antioxidant activity

Patrick C. Nobre^{^a}, Henrique A. Vargas^{^a}, Caroline G. Jacoby^{^b}, Paulo H. Schneider^{^b}, Angela M. Casaril^{^c}, Lucielli Savegnago^{^c,⁎}, Ricardo F. Schumacher^{^a}, Eder J. Lenardão^{^a}, Daiana S. Ávila^{^d}, Luiz B.L. Rodrigues Junior^{^d}, Gelson Perin^{^a,⁎}

a Laboratório de Síntese Orgânica Limpa – LASOL – CCQFA, Universidade Federal de Pelotas – UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil

b Instituto de Química, Universidade Federal do Rio Grande do Sul – UFRGS, P.O. Box 15003, 91501-970 Porto Alegre, RS, Brazil

c Grupo de Pesquisa em Neurobiotecnologia – GPN, Universidade Federal de Pelotas – UFPel, P. O. Box 354, 96010-900 Pelotas, RS, Brazil

d Grupo de Pesquisa em Bioquímica e Toxicologia em Caenorhabditis elegans – GBToxCe, Universidade Federal do Pampa – UNIPAMPA, P.O. Box 97508-000, Uruguaiana, RS, Brazil

⁎Corresponding authors at: Universidade Federal de Pelotas (UFPel), P.O. Box 354, 96010-900 Pelotas, Rio Grande do Sul, Brazil. luciellisavegnago@yahoo.com.br (Lucielli Savegnago), gelson_perin@ufpel.edu.br (Gelson Perin)

Received: 2017-6-7, Accepted: 2017-8-16, Published: 2017-01-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Abstract

We describe here the synthesis of enantiomerically pure chalcogenoethers obtained through the reaction of nucleophilic species of chalcogen (S, Se and Te), generated in situ from the respective diorganyl dichalcogenides, with (R)- and (S)-tosyl solketal. Furthermore, some of the chalcogenoethers were treated with acidic cation exchange resin Dowex-(H⁺) leading to the respective deprotected enantiomerically pure 3-phenylchalcogenyl-1,2-diols. In order to explore the biological potential of these molecules, the antioxidant activity of some organochalcogens was evaluated by several in vitro assays. Overall, the chalcogenoethers containing Te were better scavengers of DPPH and ABTS^•+ radicals, had higher ferric reducing capacity and prevented lipid peroxidation. To analyze the effects of these compounds in vivo, we used the alternative model Caenorhabditis elegans. Chalcogenoethers treatment, especially (S)- and (R)-2,2-dimethyl-4-(phenylselanylmethyl)-1,3-dioxolane, conferred protection against the mortality-induced by hydrogen peroxide. Accordingly, these chalcogenoethers were able to modulate the antioxidant enzyme catalase. Notably, the compounds did not present toxicity in worm’s reproduction. To sum up, our study demonstrated that Te- containing chalcogenoethers were promising in vitro scavengers, while Se molecules were more prone to protect against a stressor in vivo. In this sense, the antioxidant activity of chalcogenoethers, especially with Se and Te, indicates that these molecules may have biological application in an attempt to reduce the oxidative stress.

Keywords

Organochalcogen

Chiral

Chalcogenoethers

PEG-400

Antioxidant

Caenorhabditis elegans

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1 Introduction

Chalcogenoethers are important compounds both in synthesis (Comasseto and Gariani, 2009; Das et al., 2015; Gai et al., 2012; Iniu et al., 2013; Schumacher et al., 2013; Wendler and Dos Santos, 2009 ) and in biological processes (El-Shamy et al., 2015; Iwaoka, 2014; Poon et al., 2013; Santoro et al., 2014 ). Selenoethers have been shown a great potential as antitumor agent (Fernandes and Gandin, 2015; Vieira et al., 2015; Zhao et al., 2012 ), and possess in vitro activity against HIV-1 and HIV-2 in primary lymphocytes (Goudgaeon and Schinazi, 1991). In addition, they have been used as ligands in metal-promoted catalysis (Cargnelutti et al., 2015a, 2015b) and as a component of semiconductor materials (Mishra et al., 2010). Similarly, thioethers, such as 3-organylthio citronellal showed high antibacterial activity against Staphylococcus sp. (Lenardão et al., 2007) and bis(arylthio)ethers, are used as building blocks for coordination polymer (Awaleh et al., 2010).

In context of biological application of organochalcogen compounds, several evidences have qualified these molecules as promising antioxidant agents (Orian and Toppo, 2014). Through in vitro screening, our group have explored the antioxidant activity of several organochalcogens, such as semi-synthetic derivatives of chrysin (Fonseca et al., 2015), phenylselanyl-1H-1,2,3-triazole-4-carbonitriles (Savegnago et al., 2016), 3-selanyl-1H-indole and 3-selanyl-imidazo[1,2-a]pyridine (Vieira et al., 2017). It was previously reported by Nogueira et al. (2004) that selenium-containing compounds may be better nucleophiles (antioxidants) than classical antioxidants. Similarly, organotellurium compounds are also readily oxidized, which make them attractive scavengers of hydrogen peroxide, hypochloride and peroxyl radicals. However, it is important to keep in mind that sulfur is an important non-metal for biological systems due to its incorporation in several proteins and biomolecules, including antioxidant enzymes.

The presence of antioxidant defenses in the organism is required to minimize damages resulting from oxidative stress, which may impair proteins, DNA and membrane lipids and can promote cell death (Halliwell, 1996). Currently, it has been reported the involvement of oxidative stress in several pathophysiological events, including neurodegenerative disorders, cardiovascular diseases and cancer (Dalleau et al., 2013). Therefore, it is imperative to seek for new antioxidant molecules that can minimize or inhibit the oxidative damage, slowing or preventing the development of several diseases. Screening of new drugs must be done respecting the 3Rs policy (recycle, refine and reduce), which recommends the use of alternative models for primary drug evaluations. Besides in vitro assays, invertebrate animals for in vivo studies are also a great asset. One example is the nematode Caenorhabditis elegans, a suitable model to study stress resistance because of its short life and reproduction cycles, which allows high throughput screenings. Moreover, a wide variety of biochemical assays can be performed in a more economical manner and the high homology between worms and mammals systems allows predictive interpretations (Sonnhammer and Durbin, 1997).

In light with the biological relevance of chalcogenoethers, the synthesis and the application of chiral organochalcogen compounds have been growing in the recent years, mainly due to the versatility of these compounds in asymmetric transformations. They can be used, for example, in the enantioselective addition of diethyl zinc to aldehydes (Braga et al., 2005, 2008), palladium-catalyzed asymmetric allylic alkylation (Andrade et al., 2010), Baylis-Hillman reaction (Periasamy et al., 2013), asymmetric addition reaction to olefins (Tiecco et al., 2000), asymmetric selenocyclization (Tiecco et al., 2001) and bromoaminocyclization (Chen et al., 2013).

Recently, our group investigated the formation of new organochalcogen compounds containing the 1,3-dioxolane unit. We described a method for the synthesis of racemic thioethers starting from thiols and tosyl solketal in the presence of KF/Al₂O₃ and PEG-400 as the solvent (Perin et al., 2014). In that work, different thioethers were prepared starting from aromatic and aliphatic thiols and the solvent/catalytic system could be reused without previous treatment. We also described the synthesis of racemic glycerol-based chalcogenoethers (sulfide, selenide and telluride), using NaBH₄ as reducing agent and PEG-400 as a green solvent (Nobre et al., 2014). Among the synthesized chalcogenoethers, 2,2-dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane proved to be a promising antioxidant in studies in vitro. In another set of experiments, our research group described the synthesis of enantiomerically pure symmetric chalcogenides and dichalcogenides, by the reaction of the elemental chalcogenium using NaBH₄/PEG-400 or LiBHEt₃/THF as reducing system and (R)- or (S)-tosyl solketal (Borges et al., 2016).

To further investigate new protocols to access semi-synthetic compounds containing S, Se and Te, we describe here the synthesis of enantiomerically pure chalcogenoethers 3, using nucleophilic species of chalcogen generated in situ from dichalcogenides 1 and (R)- or (S)-tosyl solketal 2 in PEG-400 as solvent (Scheme 1). In addition, the antioxidant activity of the compounds (R)-3a, (S)-3a, (R)-3e, (S)-3e, (R)-3h and (S)-3h was evaluated by several in vitro and in vivo assays in order to contribute to the pursuit of better bioactive molecules with pharmacological properties.

General scheme for the synthesis of chiral chalcogenoethers 3.

2 Experimental section

2.1

2.1 Synthesis

(R)- and (S)-solketal (99% ee) were purchased from Sigma Aldrich. The reactions were monitored by TLC carried out on Merck silica gel (60 F₂₅₄) by using UV light as visualizing agent and 5% vanillin in 10% H₂SO₄ and heat as developing agents. Baker silica gel (particle size 0.040–0.063 mm) was used for flash chromatography. Hydrogen nuclear magnetic resonance spectra (¹H NMR) were obtained at 300 MHz, 400 MHz and 600 MHz. Spectra were recorded in CDCl₃ solutions. Chemical shifts are reported in ppm, referenced to tetramethylsilane (TMS) as the external reference. Coupling constant (J) are reported in Hertz. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), dd (doublet of doublet), t (triplet), quint (quintet), sex (sextet) and m (multiplet). Carbon-13 nuclear magnetic resonance spectra (¹³C NMR) were obtained at 75 MHz, 100 MHz and 150 MHz. Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl₃. Low-resolution mass spectra were obtained with a Shimadzu GC–MS-QP2010 mass spectrometer. High resolution mass spectra (HRMS) were obtained for all compounds on a LTQ Orbitrap Discovery mass spectrometer (Thermo Scientific). This hybrid system meets the LTQ XL linear ion trap mass spectrometer and an Orbitrap mass analyzer. Optical rotations were measured with a JASCO P-2000 Polarimeter in CH₂Cl₂ solutions as the solvents with percent concentrations.

2.1.1

2.1.1 General procedure for synthesis of tosyl solketal 2 (Roberge et al., 2009)

To a mixture of (R)- or (S)-solketal (1.32 g, 10 mmol), in pyridine (4.0 mL) in an ice bath was added p-toluenesulfonylchloride (2.09 g, 11 mmol) in one portion. The reaction mixture was stirred for 30 min. the ice bath was removed and the reaction mixture was stirred for 3 h. After, the reaction mixture was extracted with ethyl acetate (20.0 mL) and washed with brine (4 × 5.0 mL). The organic phase was separated, dried with MgSO₄ and the solvent was evaporated under reduced pressure. The product was isolated by column chromatography using silica gel 60A (0.060–0.200 mm-Across) and hexanes/ethyl acetate (80:20) as the eluent. The (R)- and (S)-tosyl solketal 2 were isolated in 95% and 92% yield, respectively.

2.1.2

2.1.2 General procedure for synthesis of chalcogenethers enantiomerically pure 3 (Nobre et al., 2014)

To a mixture of dichalcogenide 1 [0.3 mmol of (RY)₂], in PEG-400 (3.0 mL) under N₂ atmosphere, NaBH₄ (0.023 g, 0.6 mmol) was added at room temperature and the mixture was stirred for 30 min. Then, the tosyl solketal 2 (0.5 mmol) was added and the temperature was slowly raised to 50 °C. The reaction progress was monitored by TLC. After the time indicated on Table 1, the reaction mixture was extracted with ethyl acetate (15.0 mL) and washed with water (3 × 5.0 mL). The organic phase was separated, dried with MgSO₄ and the solvent was evaporated under reduced pressure. The product was isolated by column chromatography using silica gel and hexanes or hexanes/ethyl acetate as the eluent. The new compounds were fully characterized and the spectral data are listed below:

Table 1 Synthesis of enantiomerically pure 2,2-dimethyl-4-(chalcogenylmethyl)-1,3-dioxolanes 3 using PEG-400 as solvent.^a


Entry	Tosyl Solketal 2	RYYR 1	Product 3	Time (h)	Yield (%)^b
1				3	88
2	(R)-2			5	87
3	(R)-2			4	73
4	(R)-2			6.5	64
5	(R)-2			5	87
6	(R)-2			4	79
7	(R)-2			6	71
8	(R)-2			4	82
9		1a		3	84
10	(S)-2	1b		5	79
11	(S)-2	1c		4	76
12	(S)-2	1d		6.5	63
13	(S)-2	1e		5	79
14	(S)-2	1f		4	71
15	(S)-2	1g		6	67
16	(S)-2	1h		4	78

a Reaction conditions: Dichalcogenide 1 (0.3 mmol), tosyl solketal 2 (0.5 mmol), NaBH₄ (0.6 mmol) in PEG-400 (3.0 mL) at 50 °C in a N₂ atmosphere.

b Isolated yields.

2.1.2.1

2.1.2.1 (R)-2,2-Dimethyl-4-(phenylselanylmethyl)-1,3-dioxolane 3a

Yield: 0.120 g (88%); Yellowish oil; [α]_D²⁰: + 28.22 (c 0.36, CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ = 7.46–7.40 (m, 2H, Ar—H); 7.19–7.13 (m, 3H, Ar—H); 4.22–4.16 (m, 1H, O—CH); 3.99 (dd, J = 8.4 and 6.0 Hz, 1H, O—CHH); 3.60 (dd, J = 8.4 and 6.2 Hz, 1H, O—CHH); 3.07 (dd, J = 12.4 and 5.0 Hz, 1H, Se-CHH); 2.84 (dd, J = 12.4 and 8.2 Hz, 1H, Se-CHH); 1.33 (d, J = 0.5 Hz, 3H, C-CH₃); 1.24 (d, J = 0.6 Hz, 3 H, C-CH₃). ¹³C NMR (100 MHz, CDCl₃) δ = 132.9, 129.5, 129.2, 127.2, 109.6, 75.5, 69.3, 30.7, 27.0, 25.6. MS: m/z (rel. int.) 272 (18.2), 157 (11.8), 115 (14.6), 101 (60.5), 43 (100.0). HRMS (ESI): m/z calcd for C₁₂H₁₆O₂Se [M+OH]⁺: 289.0343; found: 289.0338.

2.1.2.2

2.1.2.2 (R)-4-(4-Methoxyphenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3b

Yield: 0.131 g (87%); Yellowish oil; [α]_D²⁰: +21.22 (c 0.47, CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ = 7.42–7.38 (m, 2H, Ar—H); 6.74–6.71 (m, 2H, Ar—H); 4.20–4.14 (m, 1H, O—CH); 3.98 (dd, J = 8.4 and 6.0 Hz, 1H, O—CHH); 3.70 (s, 3H, O—CH₃); 3.56 (dd, J = 8.4 and 6.3 Hz, 1H, O—CHH); 2.99 (dd, J = 12.3 and 5.0 Hz, 1H, Se—CHH); 2.77 (dd, J = 12.3 and 8.3 Hz, 1H, Se—CHH); 1.32 (d, J = 0.6 Hz, 3H, C—CH₃); 1.24 (d, J = 0.6 Hz, 3H, C—CH₃). ¹³C NMR (CDCl₃, 100 MHz) δ = 159.5, 135.8, 119.0, 114.9, 109.5, 75.5, 69.3, 55.2, 31.6, 27.0, 25.6. MS: m/z (rel. int.) 302 (72.1), 187 (72.1), 115 (29.4), 101 (96.4), 43 (100.0). HRMS (ESI): m/z calcd for C₁₃H₁₈O₃Se [M+OH]⁺: 319.0449; found: 319.0443.

2.1.2.3

2.1.2.3 (R)-4-(4-Fluorophenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3c

Yield: 0.106 g (73%); Yellowish oil; [α]_D²⁰: +21.62 (c 0.50, CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ = 7.44 (dd, J = 8.7 and 5.4 Hz, 2H, Ar—H); 6.89 (t, J = 8.7, 2H, Ar—H); 4.21–4.15 (m, 1H, O—CH); 4.00 (dd, J = 8.4 and 6.0 Hz, 1H, O—CHH); 3.59 (dd, J = 8.4 and 6.2 Hz, 1H, O—CHH); 3.02 (dd, J = 12.4 and 5.2 Hz, 1H, Se—CHH); 2.82 (dd, J = 12.4 and 8.0 Hz, 1H, Se—CHH); 1.34 (s, 3H, C—CH₃); 1.25 (s, 3H, C—CH₃). ¹³C NMR (CDCl₃, 100 MHz) δ = 162.5 (d, J_C-F = 246.6 Hz); 135.6 (d, J_C-F = 7.9 Hz); 123.7 (d, J_C-F = 3.3 Hz); 116.3 (d, J_C-F = 21.4 Hz); 109.6; 75.3; 69.2; 31.5; 26.9; 25.5. MS: m/z (rel. int.) 290 (39.0), 175 (35.7), 115 (11.1), 101 (83.8), 43 (100.0). HRMS (ESI): m/z calcd for C₁₂H₁₅FO₂Se [M+OH] ⁺: 307.0249; found: 307.0245.

2.1.2.4

2.1.2.4 (R)-4-Butylselanylmethyl-2,2-dimethyl-1,3-dioxolane 3d

Yield: 0.081 g (64%); Yellowish oil; [α]_D²⁰: +33.21 (c 0.48, CH₂Cl₂); ¹H NMR (CDCl₃, 600 MHz) δ = 4.25–4.20 (m, 1H, O—CH); 4.07 (dd, J = 8.3 and 6.0 Hz, 1H, O—CHH); 3.63 (dd, J = 8.3 and 6.4 Hz, 1H, O—CHH); 2.72 (dd, J = 12.4 and 5.2 Hz, 1H, CH₂—Se—Bu); 2.59–2,51 (m, 3H, CH₂—Se—CH₂); 1.58 (quint, J = 7.4 Hz, 2H, CH₂-CH₂—CH₂); 1.36 (s, 3H, C—CH₃); 1.33 (sex, J = 7.4 Hz, 2H, CH₂—CH₂—CH₃); 1.29 (s, 3H, C—CH₃); 0.85 (t, J = 7.4, 3H, CH₂—CH₃). ¹³C NMR (CDCl₃, 150 MHz) δ = 109.6, 76.0, 69.5, 32.6, 30.0, 26.4, 25.7, 24.5, 22.9, 13.6. MS: m/z (rel. int.) 252 (28.7), 101 (74.6), 43 (100.0). HRMS (ESI): m/z calcd for C₁₀H₂₀O₂Se [M+OH]⁺: 269.0656; found: 269.0653.

2.1.2.5

2.1.2.5 (R)-2,2-Dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3e

Yield: 0.140 g (87%); Redish oil; [α]_D²⁰: +17.10 (c 0.20, CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ = 7.77–7.73 (m, 2H, Ar—H); 7.32–7.18 (m, 3H, Ar—H); 4.40–4.32 (m, 1H, O—CH); 4.12 (dd, J = 8.3 and 5.9 Hz, 1H, O—CHH); 3.61 (dd, J = 8.3 and 6.5 Hz, 1H, O—CHH); 3.15 (dd, J = 11.9 and 5.1 Hz, 1H, Te—CHH); 2.98 (dd, J = 11.9 and 8.1 Hz, 1H, Te—CHH); 1.42 (d, J = 0.5 Hz, 3H, C—CH₃); 1.33 (d, J = 0.6 Hz, 3H, C—CH₃). ¹³C NMR (75 MHz, CDCl₃) δ = 138.6, 129.3, 127.9, 110.9, 109.7, 76.6, 70.4, 27.1, 25.7, 11.9. MS: m/z (rel. int.) 322 (45.5), 207 (62.5), 115 (45.7), 101 (18.2), 77 (100.0), 43 (62.6). HRMS (ESI): m/z calcd for C₁₂H₁₆O₂Te [M+OH]⁺: 339.0240; found: 339.0233.

2.1.2.6

2.1.2.6 (R)-2,2-Dimethyl-4-(4-tolyltellanylmethyl)-1,3-dioxolane 3f

Yield: 0.133 g (79%); Redish oil; [α]_D²⁰: +14.44 (c 0.57, CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ = 7.65 (d, J = 8.0 Hz, 2H, Ar—H); 7.02 (d, J = 8.0 Hz, 2H, Ar—H); 4.38–4.29 (m, 1H, O—CH); 4.10 (dd, J = 8.3 and 5.9 Hz, 1H, O—CHH); 3.59 (dd, J = 8.3 and 6.6 Hz, 1H, O—CHH); 3.11 (dd, J = 11.9 and 5.0 Hz, 1H, Te—CHH); 2.93 (dd, J = 11.9 and 8.3 Hz, 1H, Te—CHH); 2.33 (s, 3H, Ar-CH₃); 1.42 (s, 3H, C—CH₃); 1.32 (s, 3H, C—CH₃). ¹³C NMR (75 MHz, CDCl₃) δ = 139.0, 138.0, 130.2, 109.6, 106.6, 76.7, 70.3, 27.1, 25.7, 21.1, 11.8. MS: m/z (rel. int.) 336 (30.1), 221 (39.2), 115 (29.1), 101 (12.6), 91 (100.0), 43 (62.2). HRMS (ESI): m/z calcd for C₁₃H₁₈O₂Te [M+OH]⁺: 353.0396; found: 353.0376.

2.1.2.7

2.1.2.7 (R)-4-(4-Chlorophenyltellanylmethyl)-2,2-dimethyl-1,3-dioxolane 3g

Yield: 0.126 g (71%); Redish oil; [α]_D²⁰: +11.93 (c 0.57, CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ = 7.69–7.64 (m, 2H, Ar—H); 7.20–7.15 (m, 2H, Ar—H); 4.39–4.30 (m, 1H, O—CH); 4.11 (dd, J = 8.2 and 5.9 Hz, 1H, O—CHH); 3.61 (dd, J = 8.2 and 6.5 Hz, 1H, O—CHH); 3.12 (dd, J = 11.9 and 5.3 Hz, 1H, Te—CHH); 2.99 (dd, J = 11.9 and 7.7 Hz, 1H, Te—CHH); 1.42 (d, J = 0.6 Hz, 3H, C—CH₃); 1.33 (d, J = 0.5 Hz, 3H, C-CH₃). ¹³C NMR (75 MHz, CDCl₃) δ = 140.0, 134.5, 129.5, 109.8, 108.5, 76.4, 70.3, 27.0, 25.7, 12.5. MS: m/z (rel. int.) 356 (19.4), 241 (31.9), 115 (36.3), 101 (28.4), 43 (100.0). HRMS (ESI): m/z calcd for C₁₂H₁₅ClO₂Te [M+OH]⁺: 372.9850; found: 372.9831.

2.1.2.8

2.1.2.8 (R)-2,2-Dimethyl-4-(phenylthiomethyl)-1,3-dioxolane 3h

Yield: 0.092 g (82%); Yellowish oil; [α]_D²⁰: +28.16 (c 0.61, CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ = 7.39–7.35 (m, 2H, Ar—H); 7.31–7.26 (m, 2H, Ar—H); 7.22–7.17 (m, 1H, Ar—H); 4.28–4.20 (m, 1H, O—CH); 4.08 (dd, J = 8.4 and 5.7 Hz, 1H, O—CHH); 3.75 (dd, J = 8.4 and 5.8 Hz, 1H, O—CHH); 3.22 (dd, J = 13.3 and 4.7 Hz, 1H, S—CHH); 2.94 (dd, J = 13.3 and 8.1 Hz, 1H, S—CHH); 1.43 (d, J = 0.5 Hz, 3H, C—CH₃); 1.33 (d, J = 0.6 Hz, 3H, C—CH₃). ¹³C NMR (75 MHz, CDCl₃) δ = 135.4, 129.6, 129.0, 126.4, 109.6, 74.7, 68.7, 37.1, 26.9, 25.5. MS: m/z (rel. int.) 224 (38.5), 123 (13.8), 109 (16.3), 101 (88.7), 43 (100.0). HRMS (ESI): m/z calcd for C₁₂H₁₆O₂S [M+H]⁺: 225.0944; found: 225.0935.

2.1.2.9

2.1.2.9 (S)-2,2-Dimethyl-4-(phenylselanylmethyl)-1,3-dioxolane 3a

Yield: 0.114 g (84%); Yellowish oil; [α]_D²⁰: −34.15 (c 0.86, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with those of (R)-(+)-3a enantiomer.

2.1.2.10

2.1.2.10 (S)-4-(4-Methoxyphenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3b

Yield: 0.119 g (79%); Yellowish oil; [α]_D²⁰: −30.10 (c 0.48, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with of (R)-(+)-3b enantiomer.

2.1.2.11

2.1.2.11 (S)-4-(4-Fluorophenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3c

Yield: 0.110 g (76%); Yellowish oil; [α]_D²⁰: −26.66 (c 0.20, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-3c enantiomer.

2.1.2.12

2.1.2.12 (S)-4-Butylselanylmethyl-2,2-dimethyl-1,3-dioxolane 3d

Yield: 0.079 g (63%); Yellowish oil; [α]_D²⁰: −32.67 (c 0.48, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-3d-enantiomer.

2.1.2.13

2.1.2.13 (S)-2,2-Dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3e

Yield: 0.127 g (79%); Redish oil; [α]_D²⁰: −20.42 (c 0.48, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-3e-enantiomer.

2.1.2.14

2.1.2.14 (S)-2,2-Dimethyl-4-(4-tolyltellanylmethyl)-1,3-dioxolane 3f

Yield: 0.119 g (71%); Redish oil; [α]_D²⁰: −17.27 (c 0.44, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-3f-enantiomer.

2.1.2.15

2.1.2.15 (S)-4-(4-Chlorophenyltellanylmethyl)-2,2-dimethyl-1,3-dioxolane 3g

Yield: 0.119 g (67%); Redish oil; [α]_D²⁰ −18.12 (c 0.49, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-3g-enantiomer.

2.1.2.16

2.1.2.16 (S)-2,2-Dimethyl-4-(phenylthiomethyl)-1,3-dioxolane 3h

Yield: 0.087 g (78%); Yellowish oil; [α]_D²⁰: −31.97 (c 0.36, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-3h-enantiomer.

2.1.3

2.1.3 General procedure for the synthesis of 3-phenylchalcogenyl-1,2-diols 4 using Dowex-(H⁺) resin (Bergmeier and Stanchina, 1999)

To a solution of 3 (1.0 mmol) in MeOH (2.3 mL) was added Dowex® acidic ion-exchange resin (50WX8 20–50 mesh) (1.122 g) at room temperature. The reaction mixture was stirred for 5 h. Then, it was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure and the product purified by chromatographic column using a 1:1 mixture of hexanes/EtOAc. The new compounds were fully characterized and the spectral data are listed below:

2.1.3.1

2.1.3.1 (R)-3-(Phenylthio)propane-1,2-diol 4a (Yodo et al., 1988)

Yield: 0.156 g (85%); White solid, m.p. = 82–83 °C; [α]_D²⁰: −36.75 (c 0.45, CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ = 7.40–7.37 (m, 2H, Ar—H); 7.32–7.28 (m, 2H, Ar—H); 7.24–7.20 (m, 1H, Ar—H); 3.81–3.72 (m, 2H); 3.57 (dd, J = 11.1 and 5.6 Hz, 1H); 3.09 (dd, J = 13.8 and 4.8 Hz, 1H); 2.99 (dd, J = 13.8 and 8.0 Hz, 1H); 2.98 (br, 1H, OH); 2.38 (br, 1H, OH). ¹³C NMR (100 MHz, CDCl₃) δ = 134.8, 130.0, 129.1, 126.7, 69.8, 65.1, 37.7. MS: m/z (rel. int.) 184 (33.3), 123 (38.8), 109 (35.9), 43 (62.3), 40 (100.0).

2.1.3.2

2.1.3.2 (R)-3-(Phenylselanyl)propane-1,2-diol 4b

Yield: 0.211 g (91%); White solid, m.p. = 80–82 °C; [α]_D²⁰: −40.02 (c 0.47, CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz) δ = 7.53–7.51 (m, 2H, Ar—H); 7.27–7.23 (m, 3H, Ar—H); 3.82–3.77 (m, 1H); 3.71 (dd, J = 11.3 and 3.4 Hz, 1H); 3.55 (dd, J = 11.3 and 6.2 Hz, 1H); 3.05 (dd, J = 12.8 and 5.0 Hz, 1H); 2.97 (dd, J = 12.8 and 7.8 Hz, 1H); 2.59 (br, 2H, OH). ¹³C NMR (100 MHz, CDCl₃) δ = 133.0, 129.24, 129.18, 127.4, 70.6, 65.6, 32.0. MS: m/z (rel. int.) 232 (72.2), 183 (58.6), 157 (79.0), 78 (100.0), 40 (54.8). HRMS (ESI): m/z calcd for C₉H₁₂O₂Se [M+Na]⁺: 254.9900; found: 254.9885.

2.1.3.3

2.1.3.3 (R)-3-(Phenyltellanyl)propane-1,2-diol 4c

Yield: 0.056 g (40%); White solid, m.p. = 78–80 °C; [α]_D²⁰: −20.38 (c 0.57, CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ = 7.77–7.73 (m, 2H, Ar—H); 7.33–7.27 (m, 1H, Ar—H); 7.24–7.18 (m, 2H, Ar—H); 3.90–3.83 (m, 1H); 3.75 (dd, J = 11.1 and 3.4 Hz, 1H); 3.56 (dd, J = 11.1 and 6.5 Hz, 1H); 3.06 (dd, J = 12.4 and 5.3 Hz, 1H); 2.99 (dd, J = 12.4 and 7.6 Hz, 1H); 2.06 (br, 2H, OH). ¹³C NMR (75 MHz, CDCl₃) δ = 138.4, 129.3, 127.9, 111.4, 71.9, 66.5, 13.6. MS: m/z (rel. int.) 282 (23.6), 207 (30.9), 77 (100.0), 43 (21.1). HRMS (ESI): m/z calcd for C₉H₁₂O₂Te [M]+: 281.9900; found: 281.9886.

2.1.3.4

2.1.3.4 (S)-3-(Phenylthio)propane-1,2-diol 4a

Yield: 0.160 g (87%); White solid, m.p. = 81–83 °C; [α]_D²⁰: +35.32 (c 0.57, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(-)-4a-enantiomer.

2.1.3.5

2.1.3.5 (S)-3-(Phenylselanyl)propane-1,2-diol 4b

Yield: 0.209 g (90%); White solid, m.p. = 82–83 °C; [α]_D²⁰: +33.31 (c 0.49, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-4b-enantiomer.

2.1.3.6

2.1.3.6 (S)-3-(Phenyltellanyl)propane-1,2-diol 4c

Yield: 0.065 g (46%); White solid m.p. = 79–81 °C; [α]_D²⁰: +27.25 (c 0.80, CH₂Cl₂). The characterization data from NMR, MS and HRMS spectra were identical in all aspects with (R)-(+)-4c-enantiomer.

2.2

2.2 General procedure for biological assays

2.2.1

2.2.1 Antioxidant activity

The antioxidant activity of compounds (R)-3a, (S)-3a, (R)-3e, (S)-3e, (R)-3h and (S)-3h was evaluated by the following in vitro assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity, nitric oxide (NO) scavenging, hydroxyl radical (^•OH) scavenging, ferric ion reducing antioxidant power (FRAP), ferrous ion chelating activity, superoxide dismutase-like activity, inhibition of linoleic acid lipid peroxidation and quantification of reactive species (RS) assay. To the assessment of all biological activities, the compounds were diluted in dimethyl sulfoxide (DMSO).

These compounds were selected based on previous publication of our research group, which racemic mixtures of these compounds were screened for antioxidant activity in vitro (Nobre et al., 2014).

2.2.2

2.2.2 Radical scavenging activity

The stable DPPH radical is commonly used to measure in vitro antioxidant activity. Different concentrations of compounds (10–500 μM) were mixed with a methanolic solution of DPPH radical for 30 min at 30 °C. A decrease in the purple solution absorbance (at 517 nm) is an indicative of antioxidant activity (Choi et al., 2002).

The radical cation ABTS^•+ was previously generated with sodium persulfate in the presence of potassium phosphate buffer (Re et al., 1999). Different concentrations of compounds (0.1–500 µM) were mixed with the ABTS^•+ solution, and the mixture was left to stand for 30 min at room temperature. The resulting absorbance was measured at 734 nm and recorded as antioxidant capacity.

In vitro assays for the free radical scavenging capacity are usually based on the inactivation of radicals, such as hydroxyl (^•OH) and nitric oxide (NO) radicals. The NO exists in the inorganic complex sodium nitroprusside (SNP) as NO⁺, and the photodegradation of this molecule releases NO in the reaction media (Feelisch et al., 1996). To evaluate the NO-scavenging activity, the compounds (10–500 µM) were incubated with SNP (25 mM), followed by absorbance determination at 570 nm, which was referred to the absorbance of standard solutions of sodium nitrite salt previously treated with Griess reagent (Marcocci et al., 1994).

Hydroxyl radical is known to be the most reactive oxygen species and severely damages biomolecules in the body, such as lipids, proteins and DNA, resulting in cell damage (Lipinski, 2011). The hydroxyl radical scavenging activity was determined according to the method described by Smirnoff and Cumbes (1989) with some modifications.

The radical scavenging activity expressed as percent inhibition (%I) in relation to the control values was calculated according to the following equation: $% I = \frac{[1 - (As - Ac)]}{[Ac]} \times 100$

Ac is absorbance of the control (without compounds) and As is the absorbance in the presence of compounds.

2.2.3

2.2.3 Ferric ion reducing antioxidant power (FRAP)

The FRAP assay was carried out as described by Stratil et al. (2006). This assay measures the ability of compounds in reducing the ferric 2,4,6-tripyridyl-s-triazine complex [Fe³⁺-(TPTZ)₂]³⁺ to the intensely blue colored ferrous complex [Fe²⁺-(TPTZ)₂]²⁺ in acidic medium (Benzie and Strain, 1999). Different concentrations of compounds (1–500 µM) and the FRAP reagent were added to each sample and the mixture was incubated at 37 °C for 40 min in the dark. The absorbance of the resulting solution was measured at 593 nm using a spectrophotometer.

2.2.4

2.2.4 Chelating potential assay

In this assay, free ferrous ions react with triazine, forming a blue chromophore that can be measured in spectrophotometer. The compound will present chelating potential if it reacts with the ferrous ions, inhibiting the formation of the complex with the triazine and decreasing the absorbance of the sample at 470 nm. Thus, the chelating potential of compounds (10–500 μM) was determined by mixing them with FeSO₄ (2 mM) and triazine (5 mM) in HCl (40 mM). The sample solution was incubated at room temperature during 10 min in the dark.

2.2.5

2.2.5 Superoxide dismutase (SOD)-like activity

Molecules that mimic SOD act by inactivation of superoxide anion radical (O₂^•−). The SOD-like activity of compounds (10–500 μM) was determined as described by Marklund and Marklund (1974). Briefly, Tris-HCl buffer (pH 8.5) and 24 mM pyrogallol were added to the sample solution during 60 min at 37 °C. Sample activities are expressed as the auto-oxidation inhibition rate (%) of pyrogallol vs the control sample (sample without compounds).

2.2.6

2.2.6 Linoleic acid peroxidation assay

The total lipid peroxidation was estimated by the measurement of malondialdehyde (MDA) levels, which are final products of lipid peroxidation. The MDA levels were determined spectrophotometrically by the thiobarbituric acid reactive substances assay. In this test, linoleic acid was used as a lipid matrix to evaluate the effect of compounds on Fe²⁺, ascorbic acid-induced lipid peroxidation. The ability of compounds (0.05–500 µM) to inhibit linoleic acid peroxidation was determined by the method of Choi et al. (2002) with modifications. The absorbance of the organic phase was measured at 532 nm using ⁿbutanol as blank.

2.2.7

2.2.7 Assay with tissue homogenate

2.2.7.1

2.2.7.1 Tissue preparation

Swiss mice (25–30 g) were euthanized, and the cerebral tissue was rapidly removed and placed on ice. The cortex was dissected, kept chilled and homogenized in 50 mM Tris–HCl at pH 7.4 (1/4, weight/volume [w/v]). The homogenate was centrifuged for 10 min at 2500 rpm to yield a pellet that was discarded and a low-speed supernatant (S₁).

2.2.7.2

2.2.7.2 Quantification of reactive species (RS) assay in cortex

The quantification of RS levels in cortex of mice was performed according Loetchutinat et al. (2005). Briefly, different concentration of compounds (1–100 µM) were incubated with S₁, 1 mM dichloro-dihydro-fluorescein diacetate (DCHF-DA), Tris-HCl pH 7.4 and sodium azide (inhibitor of complex IV of chain electron transport (Harvey et al., 1999). The oxidation of DCFH-DA to fluorescent dichlorofluorescein (DCF) is measured for the detection of intracellular RS. Results are expressed as percentage of RS formation when compared to the sample without antioxidants (100% of RS formation).

2.2.8

2.2.8 Elegans assays

2.2.8.1

2.2.8.1 Elegans strains and handling of the worms

C. elegans Bristol N2 (wild type), GA800 (wuls151) were handled and maintained at 20° C on E. coli OP50/NGM (nematode growth media) plates, as previously described by Brenner (1974). Synchronous L1 populations were obtained by isolating embryos from gravid hermaphrodites using bleaching solution (1% NaOCl; 0.25 M NaOH), followed by washes to remove bleaching, dissolved worms and bacterial debris, according to standard procedures. All experiments were carried out at 22 °C in a humidified-controlled environment.

2.2.8.2

2.2.8.2 Dose–response curves

The lethal concentrations 50% (LC₅₀) of the six chalcogenoethers in C. elegans was determined with doses ranging from 1 µM to 1000 µM. Synchronized L1 worms (2,000) were treated for 30 min with each compound, in liquid media containing NaCl 85 mM. At the end compounds were removed by three washes with NaCl solution. Worms were placed on OP50 seeded NGM plates and dose–response curves were plotted from scoring the number of surviving worms on each dish at 48 h post-exposure.

2.2.8.3

2.2.8.3 Brood size

Synchronized L1 worms (2000) were acutely exposed to the compounds as previously described at the concentrations of 10, 50 and 250 µM. After 48 h, worms were individually transferred to individually NGM plates seeded with OP50, in triplicates. For assessing brood size, one worm for each treatment was transferred to a new plate every day, and the total number of hatched eggs on the previous plates was scored. Data were expressed as percent of control. The experiments were repeated at least three times.

2.2.8.4

2.2.8.4 Stress-resistance against hydrogen peroxide (H₂O₂)

Compounds doses below the LC10 (10% lethality) were chosen for the subsequent experiments. To assess the effect of these compounds on H₂O₂-exposed animals, we pre-treated 2,000 worms for 30 min with 1 µM and 50 µM of each compound, followed by washes to remove the compounds. Right after, these worms were exposed for additional 30 min with H₂O₂ (0.4 mM), followed by three washes in NaCl 85 mM. Next, worms were placed on OP50 seeded NGM plates. Scoring of surviving worms was performed 48 h after exposure. For all dose–response curves, scores were normalized to percentage of control (0 mM compounds/0 mM H₂O₂).

2.2.8.5

2.2.8.5 Measurement of CAT-1,2 and 3::GFP levels

To observe the levels of catalase, the transgenic strain GA800 (wuls151- ctl-1 + ctl-2 + ctl-3 + myo-2::GFP), which has catalase enzyme tagged with GFP, was used. 2,000 worms were treated with the compounds at concentrations of 1 µM and 50 µM for 30 min and placed in Petri dishes with Escherichia coli OP50. After 24 h post-treatment, images of 5 random worms per group were acquired using an EVOS FLoid Cell Imaging Station (Thermo Fisher Scientific) and the fluorescence was quantified by using ImageJ.

2.3

2.3 Statistical analysis

Data were analyzed by one-way analysis of variance (ANOVA) followed by Tukey post hoc test. The IC₅₀ values (the concentration of sample required to scavenge 50% of the free radicals) were calculated from the graph of the scavenging effect percentage versus the 100 compound concentration. Differences were considered statistically significant when p < 0.05. All tests were performed at least three times in duplicate, and data are expressed as mean ± standard deviation (S.D). All the results were analyzed using GraphPad Software version 7.0 (GraphPad Software, San Diego, CA).

3 Results and discussion

3.1

3.1 Chemistry

Based on the conditions described in our previous report for the synthesis of racemic chalcogenoethers (Nobre et al., 2014), our attention turned to the nucleophilic substitution reaction to prepare the enantiomerically pure compounds 3. Thus, different dichalcogenides 1 (0.25 mmol) were reacted with NaBH₄ (0.6 mmol) under N₂ atmosphere and using PEG-400 as the solvent to generate in situ the nucleophilic chalcogenolate species after 30 min at room temperature. After that, the (S)- or (R)- tosyl solketal 2 (0.5 mmol) was added on the reaction flask, and the temperature was slowly raised to 50 °C and the mixture stirred to this temperature for the time indicated on Table 1.

Initially we investigated the reactivity of (R)-tosyl solketal 2 in the presence of aliphatic and aromatic diselenides (Table 1, entries 1–4). In a general way, the reactions were successfully performed to give the respective (R)-selenoethers 3a-d. High yields of the expected products were obtained in shorter reaction times starting from aromatic diselenides 1a-c. As expected, the presence of an electron withdrawing group in the aromatic ring decreased the yield, thus, when of the 4-fluoro-substituted diselenide 1c was used the selenoether (R)-3c was isolated in 73% yield after 4 h (Table 1, entry 3). We also investigated this methodology using dialkyl diselenide, thus, the reaction of dibutyl diselenide 1d with (R)-2 provided to (R)-3d in 64% yield after 6.5 h (Table 1, entry 4). To extend our methodology, diphenyl ditelluride 1e and diaryl ditellurides containing electron-donating (Me) 1f and electron-withdrawing (Cl) 1g groups at the para-position were used, in this way, the respective (R)-telluroethers 3e-g were obtained in good yields after 4–6 h (Table 1, entries 5–7). Moreover, when the reaction was performed using diphenyl disulfide 1h, the corresponding (R)-thioether 3h was isolated in 82% yield after 4 h (Table 1, entry 8).

Furthermore, the present methodology was extended to the (S)-tosyl solketal 2 (Table 1, entries 9–16). As it can be seen in Table 1, all products (S)-3 were obtained in satisfactory yields. As expected, diaryl diselenides 1a-c gave better yields of the desired (S)-selenoethers 3a-c compared to the alkyl substituted (S)-selenoether 3d (Table 1, entries 9–12). The reaction of diaryl ditellurides 1e-g with (S)-2 also proved to be satisfactory, thus, the respective (S)-telluroethers 3e-g were obtained in good yields (Table 1, entries 13–15). We also examined the reaction of the (S)-solketal tosylate 2 with diphenyl disulfide 1h and the (S)-thioether 3h was obtained in 78% after 4 h (Table 1, entry 16).

A plausible mechanism for the reactions of dichalcogenides 1 with (S)- or (R)- tosyl solketal 2 using PEG-400 as solvent for formation of enantiomerically pure chalcogenethers 3 is depicted on Scheme 2. Firstly, the nucleophilic specie of chalcogen A is generated in situ, from the reaction of dichalcogenide 1 with NaBH₄/PEG-400. Finally, nucleophilic attack of chalcogenolate anion on the carbon atom of (R)- or (S)- tosyl solketal 2 results in the formation of enantiomerically pure chalcogenethers 3.

Due to the vast biological activities of organochalcogen compounds already described and with the target of prepare a new class of water-soluble chalcogenoethhers 4, we studied the deprotection of the (R)- and (S)-chalcogenoethers 3. For this purpose, we prepared a solution of compounds 3 in methanol, next, this solution was treated with the acidic cation-exchange Dowex-(H⁺) resin (Bergmeier and Stanchina, 1999) at room temperature for 5 h. By this protocol, the respective enantiomerically pure diols 4a and 4b were obtained in very good yields, however, the (R)- or (S)-1,2-diol 4c were isolated in moderate yields, the decomposition of the telluroethers 3e was observed (see Scheme 3). Finally, the (R)- and (S)-1,2-diols 4 were submitted to water solubility assays, and the (R)- and (S)-1,2-diol 4a-b showed good solubility in water (1.58 mg/mL, 1.54 mg/mL, 1.43 mg/mL and 1.38 mg/mL, respectively). However, the (R)- and (S)-1,2-diol 4c showed low solubility (0.34 mg/mL and 0,35 mg/mL, respectively) compared to 1,2-diols 4a-b.

Synthesis of (R)- and (S)-3-phenylchalcogenyl-1,2-diols 4.

3.2

3.2 Antioxidant activity

Over the past years, several enantiomers have been studied in order to clarify their biological properties, such as the pharmacokinetics (Uchida et al., 2015), antioxidant activity (Ferrari-Toninelli et al., 2010; Ficarra et al., 2016), the modulation of endothelial dysfunction and apoptosis (Xu et al., 2016). With this in mind, we evaluated the antioxidant activity of the enantiomers (R)-3a, (S)-3a, (R)-3e, (S)-3e, (R)-3h and (S)-3h. These enantiomerically pure compounds were selected for biological analysis in order to establish a comparison with the effect of the racemic mixture, previously evaluated by our research group (Nobre et al., 2014).

3.2.1

3.2.1 Radical scavenging activity

The DPPH scavenging ability has been widely used to evaluate antioxidant activity through hydrogen atom transfer, or electron transfer followed by proton transfer (Niki, 2010). The ABTS assay is based on a single electron transfer, and the reduction of ABTS^•+ radical cation can be more efficient than DPPH reduction (Prior et al., 2005). In general, both assays are widely used to investigate the antioxidant activity of synthetic (Mistry et al., 2017; Taha et al., 2019; Vieira et al., 2017 ) and natural compounds (Boutennoun et al., 2017) due to their simplicity and efficiency. Particularly, ABTS^•+ is a useful reference free radical for studies of reactions of organic radicals with sulfhydryl compounds (Wolfenden and Wilson, 1982).

Among the tested compounds, only (R)-3e and (S)-3e, which contain tellurium, were able to quench DPPH (Table 2) and ABTS^•+ (Table 3) radicals. The compound (R)-3e was effective in DPPH assay at concentrations starting from 10 µM, with IC₅₀ value (required concentration to scavenge 50% of radicals) of 344.5 ± 96.42 µM. To efficiently neutralize ABTS^•+ radical, (R)-3e required only 1 µM and the IC₅₀ was 13.06 ± 6.38 µM. Similarly, the (S)-3e started to effectively quench DPPH radical at 10 µM, but had a higher 50% inhibitory concentration (421.7 ± 57.52 µM). In the ABTS assay, the compound (S)-3e showed an IC₅₀ value of 8.77 ± 0.42 µM, initiating significant effect at 1 µM. On the other hand, none of the evaluated compounds were able to neutralize NO and OH^. radicals (data not shown).

Table 2 Evaluation of DPPH radical scavenging activity.

[ ] µM	Compounds
[ ] µM	(R)-3e	(S)-3e
10	7.65 ± 4.38	6.06 ± 4.88
50	17.79 ± 3.20^**	17.53 ± 5.96^**
100	25.27 ± 2.89^***	27.42 ± 2.78^***
500	65.36 ± 10.60^***	55.94 ± 4.96^***
IC₅₀	344.5 ± 96.42 µM	421.7 ± 57.52 µM

Values are expressed as mean ± SD of percentage of inhibition by the compound compared to the control (DMSO). IC₅₀ = concentration required to scavenge 50% of DPPH radical.

** p < 0.01 indicate significant difference when compared with control sample.

*** p < 0.001 indicate significant difference when compared with control sample.

Table 3 Evaluation of ABTS radical scavenging activity.

[ ] µM	Compounds
[ ] µM	(R)-3e	(S)-3e
0.1	2.09 ± 1.29	2.95 ± 2.36
0.5	5.22 ± 1.03	4.02 ± 1.37
1	15.34 ± 4.71^***	16.71 ± 0.45^***
5	26.09 ± 4.75^***	30.44 ± 5.21^***
10	51.42 ± 6.70^***	56.33 ± 4.46^***
50	100.00 ± 0.00^***	100.00 ± 0.00^***
IC₅₀	13.06 ± 6.38 µM	8.77 ± 0.42 µM

Values are expressed as mean ± SD of percentage of inhibition by the compound compared to the control (DMSO). IC₅₀ = concentration required to scavenge 50% of ABTS radical.

*** p < 0.001 indicate significant difference when compared with control sample.

3.2.2

3.2.2 Ferric ion reducing antioxidant power (FRAP)

Iron is an essential element that participates in several metabolic functions, such as deoxyribonucleic acid (DNA) synthesis, oxygen transport and electron transport (Abbaspour et al., 2014). Despite it biological importance, it is the most important inducer of RS formation in the human body (Piñero and Connor, 2000). Additionally, the antioxidant activity of newly synthesized compounds (Pérez-Cruz et al., 2018; Saundane and Manjunatha, 2016) is often established through their reducing ability. Based on these statement, the FRAP assay was used to estimate the reducing potential of enantiomerically pure chalcogenoethers.

In accordance with radical scavenging results, only the compounds (R)-3e and (S)-3e exhibited antioxidant activity through reduction of ferric ion (Table 4). Both compounds showed ferric-reducing ability starting at 5 µM, which followed a concentration-response relationship.

Table 4 Evaluation of ferric ion reducing antioxidant power (FRAP).

[ ] µM	Compounds
[ ] µM	(R)-3e	(S)-3e
Control	0.08 ± 0.01
1	0.12 ± 0.01	0.15 ± 0.02
5	0.25 ± 0.02^***	0.28 ± 0.01^***
10	0.38 ± 0.01^***	0.42 ± 0.06^***
25	0.62 ± 0.11^***	0.72 ± 0.04^***
50	1.11 ± 0.12^***	1.19 ± 0.12^***
100	2.00 ± 0.00^***	2.00 ± 0.00^***

Data are expressed as mean ± SD.

*** p < 0.001 when compared with control sample (FRAP solution without compounds).

Taken together, the data of radical scavenging and reducing power allow us to postulate that the antioxidant power of (R)-3e and (S)-3e is dependent on their ability to transfer electron and/or proton to unstable molecules. Moreover, these data are consistent with previous report, which the compound with tellurium was a better antioxidant than the chalcogenoethers with selenium and sulfur (Nobre et al., 2014).

3.2.3

3.2.3 Chelating potential assay and superoxide dismutase (SOD)-like activity

None of the tested organochalcogen exhibited SOD-like activity and chelating potential (data not shown). Hence, we may assume that the mechanisms underlying these assays are not involved in the antioxidant activity of the enantiomerically pure chalcogenoethers.

3.2.4

3.2.4 Linoleic acid lipid peroxidation assay

Elevated levels of MDA may reflect the presence of oxidative stress. This may lead to the opening of mitochondrial membrane permeability transition pores, deregulation of mitochondrial membrane potential, and as consequence, ATP depletion and cell death (Kon et al., 2004; Reid et al., 2005). Moreover, high levels of MDA are involved in several neurological diseases, such as Parkinson, Alzheimer and major depression (Cintron et al., 2016). Linoleic acid belongs to the family of omega (ω)-6 fatty acids, which are highly incorporated into neuronal plasma membranes (Galecki et al., 2009), and therefore, linoleic acid can be used as a lipid matrix to evaluate lipid peroxidation induced by several conditions.

Here we evaluated the oxidation of linoleic acid induced by Fe²⁺ and AA. This system generates OH^., which is the most detrimental free radical. According to the results presented in Table 5, the enantiomerically compounds (R)-3a, (S)-3a, (R)-3e, and (S)-3e inhibited lipid peroxidation, following a concentration-response relationship. The enantiomers (R)-3e and (S)-3e require a concentration of 41.50 ± 3.07 µM and 30.61 ± 9.35 µM, respectively, to inhibit 50% of lipid peroxidation. Meanwhile, compounds (R)-3h, and (S)-3h did not present significant effect in this assay (data not shown).

Table 5 Effect of chalcogenoethers against linoleic acid lipid peroxidation induced by Fe²⁺ and ascorbic acid.

% of lipid peroxidation
Compound	(R)-3a	(S)-3a	(R)-3e	(S)-3e
Control	7.32 ± 2.99	7.32 ± 2.99	7.87 ± 3.15	16.68 ± 5.51
Fe²⁺ + AA	100	100	100	100

[ ] µM
0.05	nt	nt	89.84 ± 7.03	nt
0.1	nt	nt	89.71 ± 1.80	nt
0.5	nt	nt	85.96 ± 7.0^7**	89.70 ± 7.11
1	nt	nt	85.47 ± 11.58^**	86.14 ± 9.29^**
5	95.30 ± 5.14	nt	85.81 ± 7.53^**	80.33 ± 11.18^***
10	77.34 ± 3.41^***	92.47 ± 10.33	74.54 ± 11.41^***	63.44 ± 8.79^***
50	82.56 ± 3.30^***	80.42 ± 6.56^**	17.44 ± 6.14^***	22.06 ± 9.96^***
100	80.36 ± 7.17^***	76.35 ± 3.03^**	12.11 ± 4.29^***	18.27 ± 5.60^***
500	67.99 ± 8.54^***	65.02 ± 16.14^***	11.19 ± 5.15^***	14.85 ± 3.52^***
IC₅₀	–	–	41.50 ± 3.07 µM	30.61 ± 9.35 µM

Data are expressed as mean ± SD of lipid peroxidation sample.

** p < 0.01 when compared with Fe²⁺-Ascorbic acid (AA) (pro-oxidation). IC₅₀ = concentration required to inhibit 50% of lipid peroxidation. nt = not tested. (–) = does not present IC₅₀ values.

*** p < 0.001 when compared with Fe²⁺-Ascorbic acid (AA) (pro-oxidation). IC₅₀ = concentration required to inhibit 50% of lipid peroxidation. nt = not tested. (–) = does not present IC₅₀ values.

3.2.5

3.2.5 Quantification of reactive species (RS) in cortex

The brain is highly vulnerable to oxidative stress, since it has high metabolic rate, lower antioxidant defense and high lipid content (Maes et al., 2011). Consequently, oxidative stress is been implicated in several pathological conditions, such as major depression, Alzheimer and Parkinson disease and amyotrophic lateral sclerosis (Patten et al., 2010).

Considering the need to find antioxidant molecules to supplement the antioxidant status in the brain, the present study also evaluated the capacity of compounds (R)-3a, (S)-3a, (R)-3e, (S)-3e, (R)-3h and (S)-3h in neutralizing RS formed in mice cortex. The formation of RS was induced by sodium azide, which acts by inhibiting the electron transport in Complex IV (Harvey et al., 1999). As demonstrated in Table 6, all tested compounds were able to quench RS in mice cortex. The enantiomers with selenium (R)-3a scavenged RS starting from 5 µM, while the compound (S)-3a was able to quench RS at 10 µM. Similarly to that, the chalcogenoethers (R)-3h and (S)-3h were scavengers of RS starting from 10 µM. Unlikely other antioxidant assays, the (R)-3e presented the lower antioxidant capacity among the tested compounds, quenching RS in mice cortex only at 500 µM. On the other hand, (S)-3e was able to scavenge RS starting from 10 µM, presenting a better antioxidant capacity than (R)-3e, suggesting the presence of enantioselectivity in this assay.

Table 6 Effect of chalcogenoethers against RS formation in cortex of mice induced by sodium azide.

% of RS formation
Compound	(R)-3a	(S)-3a	(R)-3e	(S)-3e	(R)-3h	(S)-3h
Control	23.72 ± 9.03	27.95 ± 8.77	36.01 ± 10.76	29.90 ± 10.08	26.00 ± 11.16	27.86 ± 3.93
Azide	100	100	100	100	100	100

[ ] µM
1	88.70 ± 0.71	nt	nt	nt	nt	nt
5	81.94 ± 12.67*	nt	nt	90.35 ± 0.17	104.6 ± 10.96	90.83 ± 7.26
10	73.55 ± 6.10^***	100.4 ± 11.79	84.44 ± 17.16	72.77 ± 5.42^***	32.25 ± 8.08^***	61.89 ± 9.54^***
50	86.04 ± 10.52*	80.57 ± 14.27*	83.95 ± 12.99	62.80 ± 15.86^***	44.67 ± 13.70^***	64.27 ± 7.07^***
100	74.96 ± 9.59^***	82.50 ± 14.37^**	80.85 ± 11.80	74.06 ± 11.45^***	44.86 ± 8.63^***	77.38 ± 10.35^***
500	50.89 ± 10.24^***	69.50 ± 8.97^***	53.25 ± 9.834^***	57.71 ± 7.74^***	51.08 ± 16.77^***	42.80 ± 11.71^***
IC₅₀	–	–	–	–	–	–

Data are expressed as mean ± SD of reactive species production.

* p < 0.05 when compared with azide (induction of reactive species formation). IC₅₀ = concentration required to inhibit 50% of lipid peroxidation. nt = not tested. (–) = does not present IC₅₀ values.

** p < 0.01when compared with azide (induction of reactive species formation). IC₅₀ = concentration required to inhibit 50% of lipid peroxidation. nt = not tested. (–) = does not present IC₅₀ values.

*** p < 0.001 when compared with azide (induction of reactive species formation). IC₅₀ = concentration required to inhibit 50% of lipid peroxidation. nt = not tested. (–) = does not present IC₅₀ values.

3.3

3.3 LC₅₀ determination

As depicted in Table 7, we found different LC₅₀ values for the compounds, indicating that the toxicity of the chalcogenoether compounds is directly associated with the different substituents. The order of toxicity was (S)-3e, (S)-3a, (R)-3a, (R)-3e, (S)-3h, (R)-3h. Hence, sulfur compounds were less toxic. Based in this assay, the chosen concentrations to proceed with the experiments were 1 μM and 50 μM, which showed low toxicity and did not cause 10% lethality compared to the control group.

Table 7 Lethal concentrations 50% (LC₅₀) for each chalcogenoether tested.

Compounds	(R)-3a	(S)-3a	(R)-3e	(S)-3e	(R)-3h	(S)-3h
Concentrations (µM)	212.6	194.1	237.6	166.6	124.8	531.1

3.4

3.4 Reproductive toxicity in worms

To examine whether the compounds could cause reprotoxicity to the worms, the progeny size was measured. Even at high concentrations, none of the six compounds caused alterations in worm's reproduction (See Supplementary Information, Fig. 45S).

3.5

3.5 Oxidative stress induced by H₂O₂

H₂O₂ caused a significant reduction in the worm’s survival, as expected due to its strong prooxidant potential. The worms pre-treated with sub lethal doses of the compounds (1 µM and 50 µM) were protected against H₂O₂- induced mortality. However, this protection was partial for tellurium and sulfur containing compounds. Only the compounds containing selenium, (S)-3a and (R)-3a, completely protected the worms from H₂O₂-induced oxidative stress (Fig. 1).

Survival following pre-treatment with compounds and post treatment with H2O2 A) telluroethers B) Selenoethers C) thioethers. Data were normalized to 100% and are expressed as mean ± SEM. # indicates significant difference p2O2 group. * indicates a significant difference to control group.

Notably, selenium plays a very important role for animal’s metabolism. Selenocysteine has been recognized as the 21st amino acid and is present in several proteins, particularly enzymes such as glutathione peroxidase and thioredoxin reductase (Tinggi, 2008). In C. elegans, studies have indicated that SeCys is present only in TRxR isoform 1 and the lack of this gene leads to molting defects, which depends on the redox system to reduce disulfide bonds in the cuticle (Gladyshev et al., 1999).

Organoselenium compounds have been extensively described by their GPX-like activity, but also ROS/RNS scavenger (Nogueira et al., 2004; Nogueira and Rocha, 2011). Particularly, it has been described that mono and diselenides can be oxidized by H₂O₂, which is important for peroxides detoxification (Nogueira and Rocha, 2011; Ribaudo et al., 2017). In addition, our group has recently demonstrated that organochalcogens containing Se, Te or S can all modulate transcription factors such as DAF-16 and SKN-1, which can increase the expression of antioxidant enzymes such as catalase, responsible for H₂O₂ detoxification (Wollenhaupt et al., 2014; Salgueiro et al., 2014; Salgueiro et al., 2017 ).

3.6

3.6 Fluorescence intensity of the catalase enzyme using the strain GA800

In order to understand the mechanisms by which the compounds could be acting against the effects of hydrogen peroxide, the transgenic strain GA800 (wuls151), which has the catalase enzyme labeled with GFP (green fluorescent protein) was used (Fig. 2). The results presented in the Fig. 2A–D demonstrate a slight increase in the fluorescence intensity, thus indicating increasing enzyme levels following treatment with the compounds. This finding suggests that chacogenoethers protection against H₂O₂ toxicity is partly due to the induced expression of CAT levels. It is possible that the compounds are stimulating other antioxidant enzymes or pathways, or acting throughout direct scavenger activity, as already evidenced by our group (Salgueiro et al., 2017).

Intensity of the catalase enzyme fluroscence in the transgenic strain GA800 after treatment with chalcogenoethers compounds containing A) Tellurium, B) Selenium C) sulfur. D) Representative images of GA800 untreated and treated worms (only the ones that increased CAT-1, 2-3 expression). Data were normalized to 100% and are expressed as mean ± SEM. * indicates significant difference p compared to control group.

As previously mentioned, the antioxidant capacity of organochalcogen compounds have been extensively explored in the past years (Nogueira et al., 2004). Sulfur is an essential component for several biological processes, since it is incorporated into amino acids, proteins and enzymes (Atmaca, 2004), and physiological and synthetic sulfur-containing molecules have been widely studied for their antioxidant properties (Nobre et al., 2014; Parcell, 2002; Zimmerman et al., 2015 ). Similarly, selenium is an essential micronutrient for human health, and in the form of selenocysteine, is a component of more than 25 selenoproteins with antioxidant activity (Tapiero et al., 2003). It has been demonstrated that the rate constants for the reaction of selenium-containing compounds with different oxidants are, in general, higher than the corresponding reactions with sulfur analogs (Carroll et al., 2015). On the other hand, little is known about the biological and pharmacological effects of organotellurium compounds. Despite that, tellurium-containing compounds are readily oxidized, making them attractive candidates as scavengers of reactive oxidizing agents (Nogueira et al., 2004). In agreement with this, we identified that the chalcogenoethers with tellurium presented the highest antioxidant potential in several assays employed here, followed by the enantiomers with selenium and sulfur. With this in mind, we presented here a simple method to obtain enantiomerically pure chalcogenoethers with promising antioxidant capacity, hoping to contribute to therapeutic interventions in several diseases related to oxidative stress.

4 Conclusions

In summary, we described here a simple method for synthesis of sixteen enantiomerically pure chalcogenoethers 3 derivated from (R)- and (S)-tosyl solketal 2, using a S_N2 reaction employing nucleophilic species of chalcogen generated in situ. The (R)- and (S)- chalcogenoethers 3 were obtained in good yields (88–63%) and short reaction times (3–6.5 h). Differently substituted easily available aryl and alkyl dichalcogenides were used and comparable results were observed. To complete our investigation, the ketal was deprotected and six new (R)- and (S)-3-chalcogenyl-1,2-diols 4 were synthesized in good yields. Moreover, the compounds (R)-3a, (S)-3a, (R)-3e, (S)-3e, (R)-3h and (S)-3h exhibited antioxidant activity.

Among these, the chalcogenoethers (R)-3e and (S)-3e were better scavengers of DPPH and ABTS^•+ radicals, had higher ferric reducing capacity and prevented lipid peroxidation. It is important to highlight that, in more complex biological assays (i.e. inhibition of lipid peroxidation and RS formation), the enantiomer (S)-3e tends to be more effective than (R)-3e, which may indicate some level of stereoselectivity that must be explored in the future. In this study we also tested the toxicity and antioxidant effects of the chalcogenoethers compounds using the in vivo model C. elegans. First, we analyzed the LD₅₀ of the compounds, which presented different results depending on the molecule inserted in the structure, according to previous studies (Salgueiro et al., 2014). As a very low toxicity to all molecules was observed, we analyzed their antioxidant potential against the pro-oxidant H₂O₂. The results showed that all compounds were able to increase the survival of the worms, although the majority had a partial effect whereas worms treated with (S)-3a and (R)-3a chalcogenoethers containing selenium depicted survival rate indistinguishable from control worms. This antioxidant power can be attributed in part to the RS scavenger potential of these compounds, as depicted in vitro, which also has been attributed to other organochalcogens (Nogueira et al., 2004). Notably, we observed that the compounds were able to modulate antioxidant enzyme catalase, which is responsible in degrading H₂O₂ into H₂O and O₂. Together, our data indicate that the enantiomerically pure chalcogenoethers described here are promising antioxidant molecules, but further mechanistics studies must be performed in order to evaluate the exact mechanism involved in the antioxidant capacity of enantiomerically pure chalcogenoethers.

Acknowledgements

The authors are grateful to CNPq, FAPERGS, CAPES and FINEP for the financial support.

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Zimmerman M.T., Bayse C., Ramoutar R., Brumaghim J., . Sulfur and selenium antioxidants: challenging radical scavenging mechanisms and developing structure-activity relationships based on metal binding. J. Inorg. Biochem.. 2015;145:30-40.
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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2017.08.007.

Appendix A

Supplementary material

Supplementary data 1

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Introduction

Experimental section

Synthesis
General procedure for biological assays
Statistical analysis

Results and discussion

Chemistry
Antioxidant activity
LC50 determination
Reproductive toxicity in worms
Oxidative stress induced by H2O2
Fluorescence intensity of the catalase enzyme using the strain GA800

Conclusions

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Synthesis of enantiomerically pure glycerol derivatives containing an organochalcogen unit: In vitro and in vivo antioxidant activity

Abstract

Abstract

Keywords

Organochalcogen

Chiral

Chalcogenoethers

PEG-400

Antioxidant

Caenorhabditis elegans

1 Introduction

2 Experimental section

2.1 Synthesis

2.1.1 General procedure for synthesis of tosyl solketal 2 (Roberge et al., 2009)

2.1.2 General procedure for synthesis of chalcogenethers enantiomerically pure 3 (Nobre et al., 2014)

2.1.2.1 (R)-2,2-Dimethyl-4-(phenylselanylmethyl)-1,3-dioxolane 3a

2.1.2.2 (R)-4-(4-Methoxyphenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3b

2.1.2.3 (R)-4-(4-Fluorophenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3c

2.1.2.4 (R)-4-Butylselanylmethyl-2,2-dimethyl-1,3-dioxolane 3d

2.1.2.5 (R)-2,2-Dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3e

2.1.2.6 (R)-2,2-Dimethyl-4-(4-tolyltellanylmethyl)-1,3-dioxolane 3f

2.1.2.7 (R)-4-(4-Chlorophenyltellanylmethyl)-2,2-dimethyl-1,3-dioxolane 3g

2.1.2.8 (R)-2,2-Dimethyl-4-(phenylthiomethyl)-1,3-dioxolane 3h

2.1.2.9 (S)-2,2-Dimethyl-4-(phenylselanylmethyl)-1,3-dioxolane 3a

2.1.2.10 (S)-4-(4-Methoxyphenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3b

2.1.2.11 (S)-4-(4-Fluorophenylselanylmethyl)-2,2-dimethyl-1,3-dioxolane 3c

2.1.2.12 (S)-4-Butylselanylmethyl-2,2-dimethyl-1,3-dioxolane 3d

2.1.2.13 (S)-2,2-Dimethyl-4-(phenyltellanylmethyl)-1,3-dioxolane 3e

2.1.2.14 (S)-2,2-Dimethyl-4-(4-tolyltellanylmethyl)-1,3-dioxolane 3f

2.1.2.15 (S)-4-(4-Chlorophenyltellanylmethyl)-2,2-dimethyl-1,3-dioxolane 3g

2.1.2.16 (S)-2,2-Dimethyl-4-(phenylthiomethyl)-1,3-dioxolane 3h

2.1.3 General procedure for the synthesis of 3-phenylchalcogenyl-1,2-diols 4 using Dowex-(H+) resin (Bergmeier and Stanchina, 1999)

2.1.3.1 (R)-3-(Phenylthio)propane-1,2-diol 4a (Yodo et al., 1988)

2.1.3.2 (R)-3-(Phenylselanyl)propane-1,2-diol 4b

2.1.3.3 (R)-3-(Phenyltellanyl)propane-1,2-diol 4c

2.1.3.4 (S)-3-(Phenylthio)propane-1,2-diol 4a

2.1.3.5 (S)-3-(Phenylselanyl)propane-1,2-diol 4b

2.1.3.6 (S)-3-(Phenyltellanyl)propane-1,2-diol 4c

2.2 General procedure for biological assays

2.2.1 Antioxidant activity

2.2.2 Radical scavenging activity

2.2.3 Ferric ion reducing antioxidant power (FRAP)

2.2.4 Chelating potential assay

2.2.5 Superoxide dismutase (SOD)-like activity

2.2.6 Linoleic acid peroxidation assay

2.2.7 Assay with tissue homogenate

2.2.7.1 Tissue preparation

2.2.7.2 Quantification of reactive species (RS) assay in cortex

2.2.8 Elegans assays

2.2.8.1 Elegans strains and handling of the worms

2.2.8.2 Dose–response curves

2.2.8.3 Brood size

2.2.8.4 Stress-resistance against hydrogen peroxide (H2O2)

2.2.8.5 Measurement of CAT-1,2 and 3::GFP levels

2.3 Statistical analysis

3 Results and discussion

3.1 Chemistry

3.2 Antioxidant activity

3.2.1 Radical scavenging activity

3.2.2 Ferric ion reducing antioxidant power (FRAP)

3.2.3 Chelating potential assay and superoxide dismutase (SOD)-like activity

3.2.4 Linoleic acid lipid peroxidation assay

3.2.5 Quantification of reactive species (RS) in cortex

3.3 LC50 determination

3.4 Reproductive toxicity in worms

3.5 Oxidative stress induced by H2O2

3.6 Fluorescence intensity of the catalase enzyme using the strain GA800

4 Conclusions

Acknowledgements

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

Suggested read for related articles:

2.1.3 General procedure for the synthesis of 3-phenylchalcogenyl-1,2-diols 4 using Dowex-(H⁺) resin (Bergmeier and Stanchina, 1999)

2.2.8.4 Stress-resistance against hydrogen peroxide (H₂O₂)

3.3 LC₅₀ determination

3.5 Oxidative stress induced by H₂O₂