Diethyl Selenodiglycolate: An Eco-Friendly Synthetic Antioxidant with Potential Application to Inflammatory Disorders

This study describes a single step, high yield and purity, ecofriendly and scalable procedure to prepare a selenium derivative (diethyl selenodiglycolate). Diethyl selenodiglycolate rapidly reduces hypochlorous acid (HOCl, second-order rate constant of 7 × 10⁷ M⁻¹ s⁻¹) to generate its corresponding selenoxide. In activated HL-60 cells, diethyl selenodiglycolate selectively reacted with HOCl (half maximal inhibitory concentration (IC₅₀) = 23.07 µM) but not with superoxide anion radical or hydrogen peroxide without any cytotoxicity. These results show that this synthetically simple selenide reacts in a very efficient and specific way with the harmful pro-oxidant HOCl being a promising compound to be applied in oxidative inflammatory-related conditions.

Keywords:
diethyl selenodiglycolate; antioxidant; inflammation; oxidative burst; hypochlorous acid

Authorship

Marcos F. Pinatto-Botelho

Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo-SP, BrazilUniversidade de São PauloBrazilSão Paulo, SP, BrazilDepartamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo-SP, Brazil

SelenoLife, Centro de Inovação, Empreendedorismo e Tecnologia (CIETEC), Instituto de Pesquisas Energéticas e Nucleares (IPEN), Universidade de São Paulo, 05508-000 São Paulo-SP, BrazilUniversidade de São PauloBrazilSão Paulo, SP, BrazilSelenoLife, Centro de Inovação, Empreendedorismo e Tecnologia (CIETEC), Instituto de Pesquisas Energéticas e Nucleares (IPEN), Universidade de São Paulo, 05508-000 São Paulo-SP, Brazil

https://orcid.org/0000-0001-9560-4664

Railmara P. da Silva

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo-SP, BrazilUniversidade de São PauloBrazilSão Paulo, SP, BrazilDepartamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo-SP, Brazil

Marcos V. L. R. Archilha

Lilian Giroldo

Aleksey E. Kuznetsov

Department of Chemistry, Universidad Técnica Federico Santa Maria, Av. Santa Maria 6400, Vitacura, 7660251 Santiago, ChileUniversidad Técnica Federico Santa MariaChileSantiago, ChileDepartment of Chemistry, Universidad Técnica Federico Santa Maria, Av. Santa Maria 6400, Vitacura, 7660251 Santiago, Chile

Flávia C. Meotti

Alcindo A. dos Santos ^**e-mail: alcindo@iq.usp.br

https://orcid.org/0000-0003-0358-610X

*e-mail: alcindo@iq.usp.br

Author Contributions

Marcos F. Pinatto-Botelho was responsible for the investigation, methodology and writing original draft; Railmara P. da Silva for the investigation and methodology; Lilian Giroldo for the writing review and editing; Marcos V. L. R. Archilha for the data curation and formal analysis; Aleksey E. Kuznetsov for the data curation and software; Flávia C. Meotti for the supevision, writing original draft, funding acquisition; and Alcindo A. dos Santos for the supevision, writing original draft and funding acquisition.

SCIMAGO INSTITUTIONS RANKINGS

Figures | Formulas

Figures (6)
Formulas (3)

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Scheme 1
Preparation of diethyl selenodiglycolate from elemental selenium (1.0 g; 12.6 mmol) in H₂O (10 mL), sodium borohydride (1.0 g; 26.5 mmol, in 10 mL of H₂O) and neat ethyl chloroacetate (3.08 g; 25.2 mmol) under ambient temperature.

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Figure 1
Kinetic data of the reaction of diethyl selenodiglycolate with HOCl.

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Scheme 2
HOCl-promoted oxidation of diethyl selenodiglycolate.

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Figure 2
(a) ⁷⁷Se NMR spectra (38 MHz, DMSO-d ₆) of oxidation product from diethyl selenodiglycolate (51 mg; 0.2 mmol in 500 µL of deuterated DMSO), selenoxide prepared by oxidation mediated by NaOCl (0.9 mol L⁻¹; 444 µL); (b) high resolution mass spectra of selenoxide, mediated by oxidation of NaOCl.

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Figure 3
Scavenger effect of diethyl selenodiglycolate against oxidants produced in the inflammatory oxidative burst in dHL-60. (a, b) HOCl; (c) superoxide anion radical; (d) hydrogen peroxide. (b) IC₅₀ was performed by nonlinear regression analysis. dHL-60 cells (1 × 10⁶) were incubated in the absence or presence of different concentrations of diethyl selenodiglycolate (0.5, 1.0, 10, 25 and 50 µM) in PBS/glucose at 37 °C and activated with PMA (100 ng mL⁻¹). Each bar represents the average ± standard error of three independent experiments. Statistical analyzes were performed using one-way analysis of variance (ANOVA) followed by Bonferroni’s post-test. The asterisk denotes a significant difference p < 0.05 when compared to the control group.

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Figure 4
Effect of compound diethyl selenodiglycolate in cell viability. Cell viability was measured using propidium iodide (PI) staining in a flow cytometry. The gate selection strategy was defined across populations using dHL-60 treated with staurosporine for non-viable cell gate selection (a) and non-treated dHL-60 as standard to select viable cell gates (b). Representative graphs of cell populations in (A) dHL-60; (B) dHL-60 + staurosporine (1 µM); (C) dHL-60 + diethyl selenodiglycolate (100 µM); (D) fluorescence intensity of PI in dHL-60 alone (red line), dHL-60 + staurosporine (orange line) and dHL-60 + diethyl selenodiglycolate (blue line). Percentage of cell viability (E) 24 or (F) 48 h after incubation with staurosporine (St) or diethyl selenodiglycolate. Each bar represents the average ± standard error of three independent experiments. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s post-test. The asterisk denotes a significant difference p < 0.05 when compared to the control group (C).

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(1)

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(2)

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(3)

Scheme 1 Preparation of diethyl selenodiglycolate from elemental selenium (1.0 g; 12.6 mmol) in H₂O (10 mL), sodium borohydride (1.0 g; 26.5 mmol, in 10 mL of H₂O) and neat ethyl chloroacetate (3.08 g; 25.2 mmol) under ambient temperature.

Figure 1 Kinetic data of the reaction of diethyl selenodiglycolate with HOCl.

Scheme 2 HOCl-promoted oxidation of diethyl selenodiglycolate.

Figure 2 (a) ⁷⁷Se NMR spectra (38 MHz, DMSO-d ₆) of oxidation product from diethyl selenodiglycolate (51 mg; 0.2 mmol in 500 µL of deuterated DMSO), selenoxide prepared by oxidation mediated by NaOCl (0.9 mol L⁻¹; 444 µL); (b) high resolution mass spectra of selenoxide, mediated by oxidation of NaOCl.

Figure 3 Scavenger effect of diethyl selenodiglycolate against oxidants produced in the inflammatory oxidative burst in dHL-60. (a, b) HOCl; (c) superoxide anion radical; (d) hydrogen peroxide. (b) IC₅₀ was performed by nonlinear regression analysis. dHL-60 cells (1 × 10⁶) were incubated in the absence or presence of different concentrations of diethyl selenodiglycolate (0.5, 1.0, 10, 25 and 50 µM) in PBS/glucose at 37 °C and activated with PMA (100 ng mL⁻¹). Each bar represents the average ± standard error of three independent experiments. Statistical analyzes were performed using one-way analysis of variance (ANOVA) followed by Bonferroni’s post-test. The asterisk denotes a significant difference p < 0.05 when compared to the control group.

Figure 4 Effect of compound diethyl selenodiglycolate in cell viability. Cell viability was measured using propidium iodide (PI) staining in a flow cytometry. The gate selection strategy was defined across populations using dHL-60 treated with staurosporine for non-viable cell gate selection (a) and non-treated dHL-60 as standard to select viable cell gates (b). Representative graphs of cell populations in (A) dHL-60; (B) dHL-60 + staurosporine (1 µM); (C) dHL-60 + diethyl selenodiglycolate (100 µM); (D) fluorescence intensity of PI in dHL-60 alone (red line), dHL-60 + staurosporine (orange line) and dHL-60 + diethyl selenodiglycolate (blue line). Percentage of cell viability (E) 24 or (F) 48 h after incubation with staurosporine (St) or diethyl selenodiglycolate. Each bar represents the average ± standard error of three independent experiments. Statistical analysis was performed using one-way ANOVA followed by Bonferroni’s post-test. The asterisk denotes a significant difference p < 0.05 when compared to the control group (C).

(1)

\frac{{yield}_{scavenger}}{{yield}_{\max} - {yield}_{scavenger}} = \frac{k_{FmocMet} [FmocMet]}{k_{scavenger} [scavenger]}

(2)

\frac{{yield}_{\max} [FmocMet]}{{yield}_{scavenger}} = \frac{k_{scavenger} [scavenger]}{k_{FmocMet}} + [FmocMet]

(3)

Σ E = Σ E 0 (products) - Σ E 0 (reac \tan ts)

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Diethyl Selenodiglycolate: An Eco-Friendly Synthetic Antioxidant with Potential Application to Inflammatory Disorders

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[1] *e-mail: alcindo@iq.usp.br