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Article

The Influence of O/S Exchange on the Biocatalytical Activity of Benzisoselenazol-3(2H)-ones

by
Magdalena Obieziurska
1,
Agata J. Pacuła
1,
Ulana Juhas
2,3,
Jędrzej Antosiewicz
2 and
Jacek Ścianowski
1,*
1
Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, 87-100 Torun, Poland
2
Department of Bioenergetics and Physiology of Exercise, Medical University of Gdansk, 1 Debinki Street, 80-211 Gdansk, Poland
3
Department of Immunology, Medical University of Gdansk, 1 Debinki Street, 80-211 Gdansk, Poland
*
Author to whom correspondence should be addressed.
Catalysts 2018, 8(11), 493; https://doi.org/10.3390/catal8110493
Submission received: 8 October 2018 / Revised: 19 October 2018 / Accepted: 22 October 2018 / Published: 25 October 2018
(This article belongs to the Special Issue Chalcogens in Catalysis: Synthesis and Biology)
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Versions Notes

Abstract

:
The crucial feature of organoselenium compounds, when considering them as promising drug candidates in cancer therapy, is their unique ability to alter the cellular redox regulations. Organic Se-molecules continue to demonstrate a positive therapeutic effect both in cancer prevention—as antioxidants, and treatment—as prooxidants. The growing interest in this field of research highlights the need to search for particular pharmacophore motifs, which could enhance the efficiency and selectivity, and decrease the toxicity of potential anticancer agents. Herein, a series of redox-active organoselenium derivatives—N-functionalized benzisoselenazol-3(2H)-thiones, has been designed and synthetized. A new synthetic pathway, with the application of Lawesson’s reagent, has been developed and efficiently applied. The key steps involving microwave irradiation facilitated performing the reaction in solvent-free conditions, shortening the reaction time and significantly improving the overall yield of the process. Six N-alkyl derivatives have been obtained and tested as antioxidant catalysts and anti-proliferative agents. The N-propyl benzisoselenazol-3(2H)-thione was the best peroxide scavenger and the N-cyclohexyl derivative exhibited the best cytotoxic activity towards prostate cancer cell line DU145.

Graphical Abstract

1. Introduction

Preservation of redox homeostasis, provided by powerful enzymatic and nonenzymatic antioxidant systems, is essential for cell viability and proper organ function. Environmental factors, UV light, air pollution and failure of the cellular antioxidant defense tools can induce redox imbalance, trigger subsequent overproduction of reactive oxygen species (ROS) and lead to oxidative stress. As physiological oxidative stress (eustress) is essential for redox regulations and signaling, the overoxidation (distress) can cause cell damage and contribute to various diseases including neurodegeneration, diabetes, hypertension and asthma. However, generation of ROS, in some cases like tissue regeneration and cancer, has a therapeutic influence [1]. Depending on the type of the pathophysiological process and also on the stage of the disease, the ability of molecules to influence the redox regulations, decreasing or increasing oxidative stress, can serve a positive impact. The “two-face” character of Selenium, able to act as an antioxidant and prooxidant, creates a good background to design new redox-active compounds with multifunctional pharmacological potential [2].
The unique properties of selenium, facile introduction, transformation and elimination from the structure of various organic species along with further numerous synthetical and biological application routs, build-up a constantly developing field of research [3,4,5,6,7]. Among all redox-active organoselenium molecules, ebselen (N-phenyl-benzisoselenazol-3(2H)-one) is still the only organoselenide admitted to clinical trial. Its mechanism of action is associated with the ability to mimic the catalytical activity of glutathione peroxidase (GPx), a selenoenzyme that protects from oxidative damage [8,9,10,11]. Ebselen 1 can directly reduce H2O2 after transformation to the corresponding selenol 3 [12,13] (Scheme 1).
According to the most probable cycle of action, the essential step is the ability of compound 1 to form a Se-S bond in compound 2 with glutathione or other endogenous thiols. This way the molecule can act as an enzyme inhibitor, forming a seleno-sulfide conjugation with a cysteine residue, and thus providing other interesting pharmacological properties. Additionally, in higher concentrations, it can be used as a prooxidant and induce apoptosis of cancer cells [14].
To increase the activity and selectivity of ebselen, various modifications of its structure were efficiently conducted by several research groups. Promising results exposed the significant potential in this field of organoselenium chemistry [15,16,17,18,19]. However, there are only few examples of derivatives bearing a sulfur atom in the place of oxygen [20]. Until now, the influence of the thiocarbonyl group on the biological activity of benzisoselenazolones has not been thoroughly evaluated. Designing a new efficient method for the synthesis of benzisoselenazolthiones would make this group of organoselenium derivatives more accessible and as a consequence enable us to thoroughly investigate the influence of this modification on the activity of benzisoselenazolones. We assumed that the exchange of the carbonyl to thiocarbonyl group, leading to the decrease of the polarity of the double bond, could influence the stability of the Se-N bond and the speed of the formation of S-Se bond.

2. Results and Discussion

All obtained derivatives are a combination of 3 structural motifs: (1) the ebselen core, essential for the GPx-like activity, ability to catalytically eliminate reactive oxygen species and influence the physiological function of proteins by forming a seleno-sulfide bond with their thiol groups; (2) a thioamide moiety, similar to the thiourea structure, an important pharmacophore in medicinal chemistry, broadly incorporated in the structure of various drugs e.g., anti-cancer, anti-bacterial and anti-viral [21]; (3) and an N-alkyl substituent that could potentially enhance the solubility of the compounds and influence the interaction of benzisoselenazolthiones with different cell structures (Scheme 2).
Previously, we had observed that the stability of the Se-N bond influences the reactivity of benzisoselenazolones. Derivatives that could be easily transformed to diselenides were the most efficient antioxidants. In contrast, compounds possessing a stable Se-N bond were weak peroxide scavengers but good anticancer agents [22]. The exchange of the carbonyl to thiocarbony group, presented in this paper, could influence the strength of the Se-N bond and the reactivity of the synthetized compounds. Additionally, the selection of different N-alkyl substituents, short, long and more sterically hindered carbon chains can enable us to choose the best chain length for achieving the highest biological activity.

2.1. Chemistry

The main synthetical goal of the study was to develop an efficient procedure, using the commonly applied Lawesson’s reagent [23] for the introduction of the sulfur atom in the structure of N-alkylbenzisoselenazolones. We have planned to obtain N-alkylbenzisoselenazolthiones by different two-step procedures: (Method A) involving the reaction of N-alkyl-o-iodobenzamides 4 with Lawesson’s reagent to obtain corresponding thioamides 5, followed by nucleophilic substitution with Li2Se2 leading to the final Se-N bond formation, and (Method B) also starting from N-alkyl-o-iodobenzamides 4, their next reaction with Li2Se2 to obtain benzisoselenazolones 6, which are then directly converted to their sulfur analogues 7 (Scheme 3).
The first step included the synthesis of carbonyl substrates for the transformation of oxygen-based functional groups to their thio-analogues. Using our previously designed procedures we have obtained a series of N-alky-o-iodobenzamides 4a–f that were further transformed, by the reaction with dilithium diselenide, into corresponding N-alkylbenzisoselenazolones 6a–f [24,25] (Scheme 4).
The treatment of amides 4a–f with Lawessons’s reagent (LR) carried out in standard conditions [26] (Method C) resulted in only moderate yields of the thioamides 5a–f. Performing the reaction with microwave irradiation in solvent-free conditions (Method D) enabled us to significantly reduce the reaction time (3 min) and obtain the final product in good yield (44–81%) (Table 1).
Obtained thioamides 5a–f were further transformed to benzisoselenazolthiones 7a–f, by the procedure using dilithium diselenide (Method E) [24]. The same series of sulfur derivatives 7a–f was synthetized by the reaction of previously obtained benzisoselenazolones 5a–f with Lawesson’s reagent (Method F). In contrast to method D, the reaction could not be performed under microwave irradiation. Decomposition of the substrate was observed and only traces of the product were isolated. High temperature and longer reaction time needed to be applied giving low to moderate reaction yields. The results of methods E and F, and overall yields of both two-step procedures A and B are presented in Scheme 5.
For all compounds besides the N-cyclohexyl derivative 7f, method A was more efficient. The newly developed procedure involving microwave irradiation improved the methodology by shortening the time and increasing the yield of the reaction.

2.2. Catalytical and Biological Activity Evaluation

The final goal of the project was to evaluate the catalytical and biological potential of benzisoselenazolthiones 7a–f. First, all derivatives were tested as antioxidants using a conventionally applied nuclear magnetic resonance spectroscopy (NMR) assay proposed by Iwaoka and co-workers [27]. The efficiency of the hydroperoxide reduction by the Se-catalyst was equal to the rate of oxidation of DTTred to DTTox. The amount of the unreacted dithiol DTTred was measured by 1H NMR spectra in specific time intervals. The results for both carbonyl 6a–f and thiocarbonyl 7a–f derivatives are collected in Table 2.
The highest reactivity was observed for the N-propyl 7b and N-3-methylbuthyl benzisoselenazolthione 7e. After 1 h for compound 7e the amount of the remaining dithiol was only 15% and in case of derivative 7b no substrate was present in the reaction mixture. Similar results were collected for corresponding oxo-derivatives 6b and 6e. In case of N-propyl benzisoselenazolthione 7b and benzisoselenazolone 6b the presence of sulfur atom instead of oxygen significantly increased the antioxidant potential. Interestingly, the high activity of compound 7e fits to our previously observed trend that derivatives possessing a 3-methylbuthyl carbon chain in their structure, like N-3-methylbuthylbenzisoselenazolone 6e [22] and N-leucine methyl ester derivative 8 [28], exhibit significantly better antioxidant potential than ebselen (Figure 1).
It can be concluded, that the presence of N-propyl and 3-methylbuthyl carbon chain in the structure of N-alkyl benzisoselenazolones and benzisoselenazolthiones improves the peroxide scavenging properties. We can assume that the selected carbon chains provide an optimal combination of steric effect, Se-N bond stability and solubility enhancement.
Next, cytotoxic activity of the obtained derivatives was evaluated by the SRB viability assay on prostate cancer cell line DU-145 and also on non-cancerous cell line PNT1A. The IC50 values for the tested benzisoselenazolthiones 7a–f, in comparison to the activity of the corresponding oxo-analogues 6a–f are presented in Table 3.
The best antiproliferative activity was observed for N-cyclohexylbenzisoselenazolthione 7f. The corresponding N-cyclohexylbenzisoselenazolon 6f was also the most efficient cytotoxic agent among the previously tested N-alkyl benzisoselenazolones [22]. However, in contrary to thio-analogue 7f, the carbonyl derivative selectively inhibited the proliferation of cancer cell line DU-145 and was not toxic to non-cancerous cell line PNT1A.

3. Materials and Methods

3.1. Chemistry

3.1.1. General

1H NMR spectra were obtained at 400 or 700 MHz and chemical shifts were recorded relative to SiMe4 (δ0.00) or solvent resonance (CDCl3 δ7.26, CD3OD δ3.31). Multiplicities were given as: s (singlet), d (doublet), dd (double doublet), ddd (double double doublet), t (triplet), dt (double triplet) and m (multiplet). The number of protons (n) for a given resonance was indicated by nH. Coupling constants were reported as a J value in Hz. 13C NMR spectra were acquired at 100.6 Hz and chemical shifts were recorded relative to solvent resonance (CDCl3 δ77.25). NMR spectra were carried out using ACD/NMR Processor Academic Edition (please see the Supplementary Materials). Commercially available solvents DMF, DCM and MeOH (Sigma Aldrich, St. Louis, MO, USA) and chemicals were used without further purification. Column chromatography was performed using Merck 40-63D 60 Å silica gel (Sigma Aldrich, St. Louis, MO, USA).

3.1.2. Synthesis of o-iodobenzamides 4a, 4b and 4d

2% NaOH (4.4 mL) was added to a solution of an amine (1.0 mmol) in DCM (2 mL). The mixture was cooled to 0 °C and o-iodobenzoic acid chloride (1.1 mmol) dissolved in DCM (3 mL) was added dropwise. The reaction mixture was stirred in room temperature for 20 h and the product was extracted with DCM. Combined organic layers were washed with saturated NaHCO3 and dried over magnesium sulfate. The solvent was removed under reduced pressure and the product was obtained as white solid. Synthesis and characterization of compounds 4c, 4e and 4f are described in our previous paper [24]

N-ethyl-o-iodobenzamide 4a

Yield: 68%; m.p. 107–109 °C; 1H NMR (400 MHz, CDCl3) δ = 1.29 (t, J = 7.2 Hz, 3H, CH3), 3.48–3.56 (m, 2H, N-CH2), 5.73 (bs, 1H, NH), 7.10 (ddd, J = 8.0, 6.8, 2.4 Hz, 1H, 1Har), 7.36–7.43 (m, 2H, 2Har), 7.86 (dd, J = 7.6, 0.8 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 14.68 (CH3), 35.01 (CH2-N), 92.42 (Car), 128.16 (CHar), 128.24 (CHar), 131.00 (CHar), 139.80 (CHar), 142.47 (Car), 169.26 (C=O) ppm [29].

N-propyl-o-iodobenzamide 4b

Yield: 80%; m.p. 105–107 °C; 1H NMR (400 MHz, CDCl3) δ = 1.04 (t, J = 7.2 Hz, 3H, CH3), 1.66–1.73 (m, 2H, CH2), 3.42–3.47 (m, 2H, N-CH2), 5.78 (bs, 1H, NH), 7.10 (ddd, J = 8.0, 6.8, 2.4 Hz, 1H, 1Har), 7.36–7.42 (m, 2H, 2Har), 7.87 (dd, J = 7.6, 0.8 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 11.53 (CH3), 22.72 (CH2), 41.83 (CH2-N), 92.38 (Car), 128.16 (CHar), 128.27 (CHar), 131.00 (CHar), 139.83 (CHar), 142.60 (Car), 169.37 (C=S) ppm [30].

N-hexyl-o-iodobenzamide 4d

Yield: 72%; m.p. 98–100 °C; 1H NMR (700 MHz, CDCl3) δ = 0.93 (t, J = 7.0 Hz, 3H, CH3), 1.30–1.35 (m, 4H, 2xCH2), 1.39–1.43 (m, 2H, CH2), 1.61–1.65 (m, 2H, CH2), 3.43–3.46 (m, 2H, N-CH2), 5.73 (bs, 1H, NH), 7.10 (ddd, J = 7.7, 7.0, 2.1 Hz, 1H, 1Har), 7.35–7.40 (m, 2H, 2Har), 7.85 (dd, J = 7.7, 0.7 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 14.03 (CH3), 22.57 (CH2), 26.68 (CH2), 29.36 (CH2), 31.47 (CH2), 40.13 (CH2-N), 92.44 (Car), 128.12 (CHar), 128.25 (CHar), 130.93 (CHar), 139.78 (CHar), 142.58 (Car), 169.32 (C=O) ppm [31].

3.1.3. Synthesis of o-iodobenzthioamides 5a–5f

Method C: To a solution of amide (1.0 mmol) in xylene (10 mL) Lawesson’s reagent (0.70 mmol) was added portionwise and the mixture was stirred overnight at 80 °C. Solvent was removed under vacuum and the resulting crude product was purified by silica gel column chromatography (solvent: Dichloromethane).
Method D: Amide (1.0 mmol) and Lawesson’s reagent (0.70 mmol) was manually mixed in a biker and placed in a household microwave oven for 3 min (700 W). The crude product was dissolved in dichloromethane, directly placed on silica and purified by silica gel column chromatography (solvent: Dichloromethane).

N-ethyl-o-iodobenzthioamide 5a

Yield: 38, 44%; m.p. 155–157 °C; 1H NMR (400 MHz, CDCl3) δ = 1.41 (t, J = 7.6 Hz, 3H, CH3), 3.83–3.90 (m, 2H, N-CH2), 7.05 (ddd, J = 8.0, 8.0, 1.6 Hz, 1H, 1Har), 7.25 (bs, 1H, NH), 7.37 (dt, J = 7.6, 1.2 Hz, 1H, 1Har), 7.45 (dd, J = 7.6, 1.2 Hz, 1H, 1Har), 7.83 (dd, J = 8.0, 1.2 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 12.97 (CH3), 41.21 (CH2-N), 92.04 (Car), 128.25 (CHar), 128.35 (CHar), 130.24 (CHar), 139.60 (CHar), 148.29 (Car), 200.88 (C=S); IR: 3158, 3042, 2973, 2930, 1548, 1449, 1398, 1336, 1298, 1259, 1231, 1053, 1017 cm−1. Elemental Anal. Calcd for C9H10INS (291.15): C, 37.13; H, 3.46. Found: C, 37.02; H, 3.41.

N-propyl-o-iodobenzthioamide 5b

Yield: 61, 73%; m.p. 128–130 °C; 1H NMR (400 MHz, CDCl3) δ = 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.79–1.88 (m, 2H, CH2), 3.77–3.82 (m, 2H, N-CH2), 7.05 (ddd, J = 8.0, 7.6, 2.0 Hz, 1H, 1Har), 7.25 (bs, 1H, NH), 7.37 (dt, J = 7.6, 1.2 Hz, 1H, 1Har), 7.45 (dd, J = 7.6, 1.6 Hz, 1H, 1Har), 7.83 (dd, J = 8.4, 1.2 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 11.73 (CH3), 21.20 (CH2), 48.04 (CH2-N), 91.92 (Car), 128.27 (CHar), 128.35 (CHar), 130.22 (CHar), 139.63 (CHar), 148.48 (Car), 201.19 (C=S); IR: 3151, 3025, 2987, 2963, 2926, 2869, 1538, 1454, 1441, 1429, 1413, 1394, 1372, 1353, 1296, 1282, 1252, 1224, 1179, 1153, 1115, 1059, 1034, 1011 cm−1. Elemental Anal. Calcd for C10H12INS (305.177): C, 39.36; H, 3.96. Found: C, 39.45; H, 3.92.

N-butyl-o-iodobenzthioamide 5c

Yield: 58, 62%; m.p. 73–75 °C; 1H NMR (700 MHz, CDCl3) δ = 1.02 (t, J = 7.7 Hz, 3H, CH3), 1.50–1.54 (m, 2H, CH2), 1.77–1.81 (m, 2H, CH2), 3.82–3.85 (m, 2H, N-CH2), 7.06 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, 1Har), 7.28 (bs, 1H, NH), 7.39 (ddd, J = 7.7, 7.0, 1.4 Hz, 1H, 1Har), 7.45 (dd, J = 7.7, 1.4 Hz, 1H, 1Har), 7.84 (dd, J = 8.4, 1.4 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 13.76 (CH3), 20.38 (CH2), 29.85 (CH2), 46.10 (CH2-N), 91.96 (Car), 128.26 (CHar), 128.35 (CHar), 130.20 (CHar), 139.62 (CHar), 148.45 (Car), 201.05 (C=S); IR: 3158, 3029, 2989, 2961, 2927, 2869, 1540, 1455, 1428, 1392, 1354, 1339, 1303, 1280, 1261, 1217, 1154, 1115, 1060, 1044, 1013 cm−1. Elemental Anal. Calcd for C11H14INS (319.204): C, 41.39; H, 4.42. Found: C, 41.34; H, 4.49.

N-hexyl-o-iodobenzthioamide 5d

Yield: 48, 58%; yellow oil; 1H NMR (400 MHz, CDCl3) δ = 0.93 (t, J = 7.2 Hz, 3H, CH3), 1.35–1.37 (m, 4H, 2xCH2), 1.44–1.51 (m, 2H, CH2), 1.76–1.83 (m, 2H, CH2), 3.79–3.84 (m, 2H, N-CH2), 7.04 (ddd, J = 9.2, 7.6, 2.0 Hz, 1H, 1Har), 7.25 (bs, 1H, NH), 7.37 (dt, J = 7.2, 0.8 Hz, 1H, 1Har), 7.44 (dd, J = 7.6, 1.6 Hz, 1H, 1Har), 7.83 (dd, J = 8.0, 1.2 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 14.01 (CH3), 22.54 (CH2), 26.84 (CH2), 27.78 (CH2), 31.42 (CH2), 46.39 (CH2-N), 91.92 (Car), 128.28 (CHar), 128.35 (CHar), 130.20 (CHar), 139.62 (CHar), 148.49 (Car), 201.05 (C=S); IR: 3193, 3045, 2953, 2925, 2854, 1581, 1521, 1459, 1429, 1391, 1337, 1306, 1281, 1257, 1239, 1220, 1195, 1159, 1114, 1100, 1070, 1015 cm−1. Elemental Anal. Calcd for C13H18INS (347.258): C, 44.96; H, 5.22. Found: C, 44.60; H, 5.30.

N-(3-methylbutyl)-o-iodobenzthioamide 5e

Yield: 26, 57%; m.p. 69–71 °C; 1H NMR (400 MHz, CDCl3) δ = 1.00 (d, J = 6.4 Hz, 6H, 2xCH3), 1.64–1.69 (m, 2H, CH2), 1.73–1.80 (m, 1H, CH), 3.79–3.84 (m, 2H, N-CH2), 7.04 (ddd, J = 8.0, 7.2, 2.0 Hz, 1H, 1Har), 7.30 (bs, 1H, NH), 7.36 (dt, J = 7.2, 1.2 Hz, 1H, 1Har), 7.40 (dd, J = 8.0, 2.0 Hz, 1H, 1Har), 7.81 (dd, J = 8.0, 1.2 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 22.48 (2xCH3), 26.14 (CH), 36.56 (CH2), 44.72 (N-CH2), 92.04 (Car), 128.21 (CHar), 128.35 (CHar), 130.20 (CHar), 139.60 (CHar), 148.39 (Car), 200.90 (C=S); IR: 3197, 3050, 2955, 2929, 2866, 1542, 1454, 1428, 1384, 1361, 1339, 1327, 1308, 1278, 1263, 1248, 1213, 1156, 1068, 1044, 1014 cm−1. Elemental Anal. Calcd for C12H16INS (333.231): C, 43.25; H, 4.84. Found: C, 43.46; H, 4.83.

N-cyclohexyl-o-iodobenzthioamide 5f

Yield: 41, 52%; m.p. 138–141 °C; 1H NMR (700 MHz, CDCl3): δ = 1.25–1.31 (m, 1H, CH), 1.37–1.41 (m, 2H, CH2), 1.47–1.54 (m, 2H, CH2), 1.69–1.72 (m, 1H, CH), 1.81–1.84 (m, 2H, CH2), 2.27–2.28 (m, 2H, CH2), 7.54–7.58 (m, 1H, CH), 7.05 (dt, J = 7.0, 1.4 Hz, 1H, 1Har), 7.14 (bs, 1H, NH), 7.38 (dt, J = 7.0, 0.7 Hz, 1H, 1Har), 7.45 (dd, J = 7.7, 1.4 Hz, 1H, 1Har), 7.84 (dd, J = 9.1, 1.4 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 25.64 (2xCH2), 26.49 (CH2), 32.33 (2xCH2), 55.66 (CH-N), 92.84 (Car), 129.24 (CHar), 129.35 (CHar), 131.11 (CHar), 140.62 (CHar), 149.45 (Car), 200.54 (C=S) ppm; IR: 3202, 3039, 2924, 2852, 1533, 1459, 1445, 1426, 1382, 1358, 1344, 1309, 1277, 1260, 1251, 1227, 1152, 1093, 1044, 1013 cm−1. Elemental Anal. Calcd for C13H16INS (345.242): C, 45.23; H, 4.67. Found: C, 45.63; H, 4.53.

3.1.4. Synthesis of Benzisoselenazol-3(2H)-ones 6a, 6b and 6d

Hydrazine hydrate (8.0 mmol) was added dropwise to the mixture of selenium powder (1.2 mmol) and lithium hydroxide (3.6 mmol) in DMF (3 mL). Reaction was heated to 120 °C and stirred for 15 min under argon atmosphere. After cooling to room temperature, the amide (1.0 mmol) in DMF (2 mL) was added. The reaction mixture was heated to 120 °C and stirred for 20 h under argon atmosphere. The solution was cooled, 25 mL of brine was added and the mixture was stirred for an additional 20 h. Precipitate was filtered under vacuum, washed with water and dried in air. The crude product was purified by column chromatography (silica gel, DCM). Synthesis and characterization of compounds 6c, 6e and 6f are described in our previous paper [24].

N-ethyl-1,2-benzisoselenazol-3(2H)-one 6a

Yield: 68%; m.p. 93–96 °C, (lit. [32] m.p. 92–94 °C); 1H NMR (400 MHz, CDCl3) δ = 1.34 (t, J = 7.2 Hz, 3H, CH3), 3.88–3.93 (m, 2H, N-CH2), 7.41 (ddd, J = 7.6, 7.2, 1.2 Hz, 1H, 1Har), 7.57 (ddd, J = 7.6, 7.2, 1.2 Hz, 1H, 1Har), 7.66 (dt, J = 8.0, 0.8 Hz, 1H, 1Har), 8.04 (ddd, J = 8.0, 1.2, 0.8, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 15.66 (CH3), 39.85 (CH2-N), 124.09 (CHar), 126.17 (CHar), 127.72 (Car), 128.71 (CHar), 131.83 (CHar), 137.68 (Car), 166.93 (C=O) ppm; 77Se (76.3 MHz, CDCl3), δ = 877.01 ppm.

N-propyl-1,2-benzisoselenazol-3(2H)-one 6b

Yield: 81%; m.p. 71–71 °C, (lit. [32] m.p. 70–72 °C); 1H NMR (700 MHz, CDCl3) δ = 1.00 (t, J = 7.7 Hz, 3H, CH3), 1.73–1.79 (m, 2H, CH2), 3.83 (t, J = 7.7 Hz, 2H, N-CH2), 7.42 (ddd, J = 7.0, 7.0, 0.7 Hz, 1H, 1Har), 7.58 (ddd, J = 7.0, 7.0, 1.4 Hz, 1H, 1Har), 7.63 (dd, J = 9.1, 1.4 Hz, 1H, 1Har), 8.05 (dd, J = 7.7, 0.7 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 11.16 (CH3), 23.89 (CH2), 46.47 (CH2-N), 123.92 (CHar), 126.17 (CHar), 127.67 (Car), 128.87 (CHar), 131.84 (CHar), 137.63 (Car), 167.20 (C=O) ppm; 77Se (76.3 MHz, CDCl3), δ = 884.45 ppm.

N-hexyl-1,2-benzisoselenazol-3(2H)-one 6d

Yield: 72%; m.p. 83–85 °C, (lit. [33] m.p. 84–85 °C); 1H NMR (400 MHz, CDCl3) δ = 0.90 (t, J = 7.2 Hz, 3H, CH3), 1.32–1.43 (m, 6H, 3xCH2), 1.70–1.77 (m, 2H, CH2), 3.87 (t, J = 7.2 Hz, 2H, N-CH2), 7.41–7.46 (m, 1H, 1Har), 7.59 (dt, J = 6.8, 1.6 Hz, 1H, 1Har), 7.65 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H, 1Har), 8.05 (ddd, J = 8.0, 1.2, 0.8 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 13.99 (CH3), 22.50 (CH2), 26.30 (CH2), 30.55 (CH2), 31.45 (CH2), 44.89 (CH2-N), 123.93 (CHar), 126.16 (CHar), 127.70 (Car), 128.84 (CHar), 131.82 (CHar), 137.64 (Car), 167.13 (C=O) ppm; 77Se (76.3 MHz, CDCl3), δ = 883.31 ppm.

3.1.5. Synthesis of Benzisoselenazol-3(2H)-thiones 7a–7f

Method E: Hydrazine hydrate (8.0 mmol) was added dropwise to the mixture of selenium powder (1.2 mmol) and lithium hydroxide (3.6 mmol) in DMF (3 mL). Reaction was heated to 120 °C and stirred for 15 min under argon atmosphere. After cooling to room temperature, the thioamide (1.0 mmol) in DMF (2 mL) was added. The reaction mixture was heated to 120 °C and stirred for 20 h under argon atmosphere. The solution was cooled, 25 mL of brine was added and the mixture was stirred for additional 20 h. The crude product was extracted with DCM combined organic layers were washed with water to remove DMF, dried with magnesium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, DCM/hexane, 80:20).
Method F: To a solution of benzisoselenazolone (1.0 mmol) in toluene (10 mL) Lawesson’s reagent (0.70 mmol) was added portionwise and the mixture was stirred overnight at 120 °C. Solvent was removed under vacuum and the resulting crude product was purified by silica gel column chromatography (solvent: CHCl3).

N-ethyl-1,2-benzisoselenazol-3(2H)-thione 7a

Yield: 34, 21%; yellow oil; 1H NMR (400 MHz, CDCl3) δ = 1.48 (t, J = 7.2 Hz, 3H, CH3), 3.57–3.61 (m, 2H, N-CH2), 7.35 (t, J = 7.2 Hz, 1H, 1Har), 7.48 (t, J = 6.8 Hz, 1H, 1Har), 7.55 (d, J = 8.0 Hz, 1H, 1Har), 8.08 (bs, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 16.48 (CH3), 51.33 (CH2-N), 126.79 (CHar), 126.93 (CHar), 129.45 (CHar), 132.33 (CHar), 135.30 (Car), 140.96 (Car), 164.91 (C=S) ppm; 77Se (76.3 MHz, CDCl3), δ = 527.74 ppm [20].

N-propyl-1,2-benzisoselenazol-3(2H)-thione 7b

Yield: 62, 32%; yellow oil; 1H NMR (700 MHz, CDCl3) δ = 1.10 (t, J = 7.0 Hz, 3H, CH3), 1.88–1.93 (m, 2H, CH2), 3.50 (t, J = 7.0 Hz, 2H, N-CH2), 7.35 (t, J = 7.0 Hz, 1H, 1Har), 7.47 (t, J = 7.0 Hz, 1H, 1Har), 7.56 (d, J = 8.4 Hz, 1H, 1Har), 8.09 (bs, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 12.22 (CH3), 23.95 (CH2), 57.82 (CH2-N), 125.80 (CHar), 125.85 (CHar), 128.45 (CHar), 131.20 (CHar), 134.45 (Car), 139.95 (Car), 163.81 (C=S) ppm; 77Se (76.3 MHz, CDCl3), δ = 525.91 ppm [20].

N-butyl-1,2-benzisoselenazol-3(2H)-thione 7c

Yield: 40, 38%; yellow oil; 1H NMR (700 MHz, CDCl3) δ = 0.99 (t, J = 7.0 Hz, 3H, CH3), 1.48–1.53 (m, 2H, CH2), 1.80–1.84 (m, 2H, CH2), 3.51 (t, J = 7.0 Hz, 2H, N-CH2), 7.31 (dt, J = 7.7, 0.7 Hz, 1H, 1Har), 7.43 (td, J = 8.4, 1.4 Hz, 1H, 1Har), 7.51 (d, J = 7.7 Hz, 1H, 1Har), 8.05 (bs, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 13.97 (CH3), 20.80 (CH2), 32.67 (CH2), 55.77 (CH2-N), 125.82 (CHar), 125.87 (CHar), 128.45 (CHar), 131.23 (CHar), 134.44 (Car), 139.96 (Car), 163.95 (C=S) ppm; 77Se (76.3 MHz, CDCl3), δ = 526.60 ppm [20].

N-hexyl-1,2-benzisoselenazol-3(2H)-thione 7d

Yield: 51, 20%; yellow oil; 1H NMR (700 MHz, CDCl3) δ = 0.91 (t, J = 7.0 Hz, 3H, CH3), 1.33–1.38 (m, 4H, 2xCH2), 1.45–1.50 (m, 2H, CH2), 1.81–1.85 (m, 2H, CH2), 3.50 (t, J = 7.0 Hz, 2H, N-CH2), 7.31 (t, J = 7.7 Hz, 1H, 1Har), 7.44 (t, J = 7.0 Hz, 1H, 1Har), 7.52 (d, J = 7.7 Hz, 1H, 1Har), 8.02 (bs, 1H, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 14.10 (CH3), 22.67 (CH2), 27.34 (CH2), 30.51 (CH2), 31.69 (CH2), 56.13 (CH2-N), 125.79 (CHar), 125.88 (CHar), 128.47 (CHar), 131.24 (CHar), 134.41 (Car), 139.94 (Car), 163.67 (C=S) ppm; 77Se (76.3 MHz, CDCl3), δ = 525.70 ppm; IR: 3048, 3009, 2952, 2922, 2853, 1606, 1582, 1555, 1460, 1434, 1402, 1375, 1347, 1314, 1299, 1278, 1254, 1241, 1200, 1159, 1121, 1078, 1041, 1016 cm−1. Elemental Anal. Calcd for C13H17NSSe (298.306): C, 52.34; H, 5.74. Found: C, 52.03; H, 5.65.

N-(3-methylbutyl)-1,2-benzisoselenazol-3(2H)-thione 7e

Yield: 43, 25%; yellow oil; 1H NMR (700 MHz, CDCl3) δ = 0.99 (d, J = 7.0 Hz, 6H, 2xCH3), 1.72–1.75 (m, 2H, CH2), 1.80–821. (m, 1H, CH), 3.53 (t, J = 7.0 Hz, 2H, N-CH2), 7.31 (t, J = 7.7 Hz, 1H, 1Har), 7.43 (dt, J = 7.7, 0.7 Hz, 1H, 1Har), 7.52 (d, J = 8.4 Hz, 1H, 1Har), 8.03 (bs, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3) δ = 22.63 (2xCH3), 26.34 (CH), 39.34 (CH2), 54.31 (CH2-N), 125.79 (CHar), 125.87 (CHar), 128.46 (CHar), 131.22 (CHar), 134.44 (Car), 139.96 (Car), 163.83 (C=S) ppm; 77Se (76.3 MHz, CDCl3), δ = 526.38 ppm; IR: 2952, 2922, 2866, 1608, 1582, 1523, 1460, 1437, 1383, 1364, 1327, 1299, 1265, 1218, 1158, 1128, 1047, 1023, 1007 cm−1. Elemental Anal. Calcd for C12H15NSSe (284.279): C, 50.70; H, 5.32. Found: C, 50.41; H, 5.37.

N-cyclohexyl-1,2-benzisoselenazol-3(2H)-thione 7f

Yield: 35, 53%; yellow oil; 1H NMR (400 MHz, CDCl3): δ = 1.33–1.38 (m, 1H, CH), 1.38–1.50 (m, 2H, CH2), 1.54–1.62 (m, 2H, CH2), 1.69–1.72 (m, 1H, CH), 1.85–1.95 (m, 4H, 2xCH2), 3.45–3.52 (m, 1H, N-CH), 7.31 (dt, J = 8.0, 1.2 Hz, 1H, 1Har), 7.44 (dt, J = 6.8, 1.2 Hz, 1H, 1Har), 7.51 (d, J = 8.0 Hz, 1H, 1Har), 8.05 (d, J = 7.2 Hz, 1H, 1Har) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 24.67 (2xCH2), 25.79 (CH2), 32.78 (2xCH2), 65.60 (CH-N), 125.75 (CHar), 125.81 (CHar), 128.82 (CHar), 131.20 (CHar), 134.68(Car), 139.77 (Car), 161.22 (C=S) ppm; 77Se (76.3 MHz, CDCl3), δ = 514.27 ppm; IR: 2926, 2850, 1438, 1384, 1345, 1277, 1257, 1240, 1127, 1099, 1019 cm−1. Elemental Anal. Calcd for C13H15NSSe (296.290): C, 52.70; H, 5.10. Found: C, 52.97; H, 5.04.

3.2. Biological Activity Evaluation

3.2.1. Antioxidant Activity Assay

To a solution of compounds and 16–25 (0.015 mmol) and dithiothreitole DTTred (0.15 mmol) in 1.1 mL of CD3OD 30% H2O2 (0.15 mmol) was added. 1H NMR spectra were measured right after the addition of hydrogen peroxide and then in specific time intervals. The concentration of the substrate was determined according to the changes in the integration on the 1H NMR spectra. [27]

3.2.2. SRB viability Assay

Cell Culture

The prostate cancer cell line DU-145 was purchased from the American Type Culture Collection (ATTC, Manassas, VA, USA). The DU-145 cells were cultured in MEME medium supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin, 2 mM glutamine and 1 mM sodium pyruvate at 37 °C. The PNT1A cells were cultured in RPMI 1640 supplemented with serum, L-glutamine and antibiotics. The cells were maintained at 37 °C in an atmosphere containing 5% CO2. Stock solutions of N-substituted ebselen derivatives were prepared in (0.1%) DMSO.

SRB Assay

Cell viability was measured by Sulphorhodamine B (SRB) assay. The cells were grown to sub-confluent levels at the certain culture medium and then seeded into 96-well plates at 6.0 × 103 cells/well in the final volume of 200 µL in the culture medium for 24 h. Then, they were treated with various concentrations (2.5, 5, 10, 20, 30, 40 µL) of N-substituted ebelsen derivatives for the next 24 h. After incubation, the cells were fixed in 20% trichloroacetic acid for an 1 h. The plates were washed with distilled water and 0.4% SRB (Sigma Aldrich, St. Louis, MO, USA) in 1% acetic acid solution was added to the plates for 15 min. The SRB solution was washed with 1% acetic acid. SRB was then solubilized in 10 mM Trisma-base solution and the absorbance was measured at 570 nm using an automated microplate reader. The experiments were done in triplates and the IC50 values were calculated.

4. Conclusions

We have designed a new efficient two-step method to obtain a series of N-alkyl benzisoselenazol-3(2H)-thiones. The first step involving the conversion of N-substituted benzamides to their thiocarbonyl analogues has been significantly upgraded by applying microwave irradiation. The further conversion to corresponding benzisoselenazolthiones was efficiently conducted by our previously presented procedure using dilithium diselenide as the nucleophile. We have obtained a series of N-alkyl benzisoselenazolthiones and tested them as catalysts for H2O2 reduction, using a commonly used DTT assay, and cytotoxic agents on prostate cancer cell line DU145 and non-cancerous cell line PNT1A. The N-propyl 7b and N-3-methylbuthyl benzisoselenazolthione 7e were the most efficient antioxidants. In comparison to the previously tested corresponding carbonyl derivatives, it can be concluded that propyl and 3-methylbuthyl carbon chains, and the introduction of the sulfur atom increase the ability to catalytically reduce H2O2. The highest anti-proliferative activity was evaluated for N-cyclohexylbenzisoselenazolthione 7f. This result proves our previous observation, concerning the cytotoxic activity of N-alkylbenzisoselenazolones, that the presence of the N-cyclohexyl moiety is correlated with high cytotoxic potential.

Supplementary Materials

Supplementary materials are available online.

Author Contributions

Conceptualization, J.Ś.; Data curation, M.O. and A.J.P.; Formal analysis, M.O. and A.J.P.; Investigation, M.O., A.J.P., U.J. and J.A.; Writing—original draft, A.J.P.; Writing—review & editing, J.Ś.

Funding

This work was supported by the National Science Centre, Poland, grant No. UMO-2015/17/ B/NZ7/03058.

Acknowledgments

Dedicated to Janusz Zakrzewski on the occasion of his 70th birthday.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 08 00493 sch001 550
Scheme 1. Mechanism of peroxide reduction by ebselen.
Scheme 1. Mechanism of peroxide reduction by ebselen.
Catalysts 08 00493 sch001
Catalysts 08 00493 sch002 550
Scheme 2. General structure of the designed molecules.
Scheme 2. General structure of the designed molecules.
Catalysts 08 00493 sch002
Catalysts 08 00493 sch003 550
Scheme 3. Methods A and B used to obtain thio-derivatives 7.
Scheme 3. Methods A and B used to obtain thio-derivatives 7.
Catalysts 08 00493 sch003
Catalysts 08 00493 sch004 550
Scheme 4. Synthesis of carbonyl substrates.
Scheme 4. Synthesis of carbonyl substrates.
Catalysts 08 00493 sch004
Catalysts 08 00493 sch005 550
Scheme 5. Synthesis of N-alkylbenzselenazolthiones.
Scheme 5. Synthesis of N-alkylbenzselenazolthiones.
Catalysts 08 00493 sch005
Catalysts 08 00493 g001 550
Figure 1. Graphical comparison of antioxidant activities.
Figure 1. Graphical comparison of antioxidant activities.
Catalysts 08 00493 g001
Table
Table 1. Thioamide synthesis—Method C and D.
Table 1. Thioamide synthesis—Method C and D.
Catalysts 08 00493 i001
N-Substituted o-IodobenzothioamidesYield (%)
Method CMethod D
5a3844
5b6173
5c5882
5d4858
5e2657
5f2281
Table
Table 2. Results of the antioxidant activity assay.
Table 2. Results of the antioxidant activity assay.
Catalysts 08 00493 i002
Remaining Dithiotreitol (%)
Catalyst [0.1 equiv.]3 min5 min15 min30 min60 min
Benzisoselenazolones
6a8780655646
6b7757382615
6c8159413229
6d9284817875
6e7758422813
6f7569625544
Benzisoselenazolthiones
7a9997969593
7b4321320
7c9797969695
7d9998989897
7e4026181715
7f9084746547
Ebselen (1)8475645852
Table
Table 3. Cytotoxic activity evaluated in vitro.
Table 3. Cytotoxic activity evaluated in vitro.
CompoundDU-145PNT1A
IC50, µM
6a30.0620.68
6b30.21>60
6c20.76>40
6e30.39>40
6f5.71>40
7a15.3320.29
7b20.3620.77
7f10.75.63
40 µM (Cell Viability (%))
6d51.42995.669
7c52.16158.060
7d56.82965.027
7e61.17760.74

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MDPI and ACS Style

Obieziurska, M.; Pacuła, A.J.; Juhas, U.; Antosiewicz, J.; Ścianowski, J. The Influence of O/S Exchange on the Biocatalytical Activity of Benzisoselenazol-3(2H)-ones. Catalysts 2018, 8, 493. https://doi.org/10.3390/catal8110493

AMA Style

Obieziurska M, Pacuła AJ, Juhas U, Antosiewicz J, Ścianowski J. The Influence of O/S Exchange on the Biocatalytical Activity of Benzisoselenazol-3(2H)-ones. Catalysts. 2018; 8(11):493. https://doi.org/10.3390/catal8110493

Chicago/Turabian Style

Obieziurska, Magdalena, Agata J. Pacuła, Ulana Juhas, Jędrzej Antosiewicz, and Jacek Ścianowski. 2018. "The Influence of O/S Exchange on the Biocatalytical Activity of Benzisoselenazol-3(2H)-ones" Catalysts 8, no. 11: 493. https://doi.org/10.3390/catal8110493

APA Style

Obieziurska, M., Pacuła, A. J., Juhas, U., Antosiewicz, J., & Ścianowski, J. (2018). The Influence of O/S Exchange on the Biocatalytical Activity of Benzisoselenazol-3(2H)-ones. Catalysts, 8(11), 493. https://doi.org/10.3390/catal8110493

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