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Michelini, F.M.; Bueno, C.A.; Molinari, A.M.; Galigniana, M.D.; Galagovsky, L.R.; Alché, L.E.; Ramírez, J.A. "Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors" (2016) Biochimica et Biophysica Acta - General Subjects. 1860(1):129-139
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Abstract:

Background We have previously shown that some synthetic hydroxylated stigmastanes derived from plant sterols inhibit in vitro HSV-1 replication in ocular cell lines and decrease cytokine production in stimulated macrophages, suggesting that these steroids might combine antiviral and immunomodulating properties. In this paper we report the synthesis of some analogs fluorinated at C-6 in order to study the effect of this modification on bioactivity. Methods The following methods were used: organic synthesis of fluorinated analogs, cytotoxicity determination with MTT assays, cytokine production quantification with ELISAs, glucocorticoid activity determination by displacement assays, immunofluorescence and transcriptional activity assays, studies of the activation of signaling pathways by Western blot, antiviral activity evaluation through virus yield reduction assays. Results We report the chemical synthesis of new fluorinated stigmastanes and show that this family of steroidal compounds exerts its immunomodulating activity by inhibiting ERK and Akt signaling pathways, but do not act as glucocorticoids. We also demonstrate that fluorination enhances the antiviral activity. Conclusions Fluorination on C-6 did not enhance the anti-inflammatory effect, however, an increase in the in vitro antiviral activity was observed. Thus, our results suggest that it is possible to introduce chemical modifications on the parent steroids in order to selectively modulate one of the effects. General significance This family of steroids could allow the development of an alternative treatment for ocular immunopathologies triggered by HSV-1, without the undesirable side effects of the currently used drugs. © 2015 Elsevier B.V. All rights reserved.

Registro:

Documento: Artículo
Título:Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
Autor:Michelini, F.M.; Bueno, C.A.; Molinari, A.M.; Galigniana, M.D.; Galagovsky, L.R.; Alché, L.E.; Ramírez, J.A.
Filiación:Laboratorio de Virología: Agentes Antivirales y Citoprotectores, Departamento de Química Biológica, IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
IBYME (CONICET), Departamento de Química Biológica, IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
Departamento de Química Orgánica, UMYMFOR (CONICET - Facultad de Ciencias Exactas y Naturales), Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina
Palabras clave:Antiherpetic; Cytokines; Fluorinated steroids; Signaling pathways; Synthetic steroids; aldosterone; corticosterone; cytokine; dexamethasone; glucocorticoid receptor; interleukin 6; mitogen activated protein kinase; protein kinase B; stigmastane derivative; stigmasterol; tumor necrosis factor alpha; unclassified drug; antivirus agent; cytokine; glucocorticoid receptor; immunologic factor; mitogen activated protein kinase; protein kinase B; sitosterol derivative; stigmasterol; animal cell; animal tissue; antiviral activity; Article; controlled study; cytokine production; cytotoxicity; drug receptor binding; drug structure; drug synthesis; EC50; enzyme inhibition; fluorination; Herpes simplex virus 1; human; human cell; immunomodulation; in vitro study; male; mouse; nonhuman; priority journal; rat; signal transduction; animal; antagonists and inhibitors; biosynthesis; Chlorocebus aethiops; drug effects; HEK293 cell line; immunology; macrophage; metabolism; physiology; signal transduction; Vero cell line; Animals; Antiviral Agents; Cercopithecus aethiops; Cytokines; Extracellular Signal-Regulated MAP Kinases; HEK293 Cells; Herpesvirus 1, Human; Humans; Immunologic Factors; Macrophages; Proto-Oncogene Proteins c-akt; Receptors, Glucocorticoid; Signal Transduction; Sitosterols; Stigmasterol; Vero Cells
Año:2016
Volumen:1860
Número:1
Página de inicio:129
Página de fin:139
DOI: http://dx.doi.org/10.1016/j.bbagen.2015.10.024
Título revista:Biochimica et Biophysica Acta - General Subjects
Título revista abreviado:Biochim. Biophys. Acta Gen. Subj.
ISSN:03044165
CODEN:BBGSB
CAS:aldosterone, 52-39-1, 6251-69-0; corticosterone, 50-22-6; dexamethasone, 50-02-2; mitogen activated protein kinase, 142243-02-5; protein kinase B, 148640-14-6; stigmasterol, 83-48-7; Antiviral Agents; Cytokines; Extracellular Signal-Regulated MAP Kinases; Immunologic Factors; Proto-Oncogene Proteins c-akt; Receptors, Glucocorticoid; Sitosterols; Stigmasterol
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03044165_v1860_n1_p129_Michelini

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Citas:

---------- APA ----------
Michelini, F.M., Bueno, C.A., Molinari, A.M., Galigniana, M.D., Galagovsky, L.R., Alché, L.E. & Ramírez, J.A. (2016) . Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors. Biochimica et Biophysica Acta - General Subjects, 1860(1), 129-139.
http://dx.doi.org/10.1016/j.bbagen.2015.10.024
---------- CHICAGO ----------
Michelini, F.M., Bueno, C.A., Molinari, A.M., Galigniana, M.D., Galagovsky, L.R., Alché, L.E., et al. "Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors" . Biochimica et Biophysica Acta - General Subjects 1860, no. 1 (2016) : 129-139.
http://dx.doi.org/10.1016/j.bbagen.2015.10.024
---------- MLA ----------
Michelini, F.M., Bueno, C.A., Molinari, A.M., Galigniana, M.D., Galagovsky, L.R., Alché, L.E., et al. "Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors" . Biochimica et Biophysica Acta - General Subjects, vol. 1860, no. 1, 2016, pp. 129-139.
http://dx.doi.org/10.1016/j.bbagen.2015.10.024
---------- VANCOUVER ----------
Michelini, F.M., Bueno, C.A., Molinari, A.M., Galigniana, M.D., Galagovsky, L.R., Alché, L.E., et al. Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors. Biochim. Biophys. Acta Gen. Subj. 2016;1860(1):129-139.
http://dx.doi.org/10.1016/j.bbagen.2015.10.024