Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors

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...

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Autores principales:	Michelini, Flavia Mariana, Bueno, Carlos Alberto, Alche, Laura Edith, Ramirez, Javier Alberto
Publicado:	2016
Materias:	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 immunologic factor sitosterol derivative 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 Vero cell line Animals Antiviral Agents Cercopithecus aethiops 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
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03044165_v1860_n1_p129_Michelini http://hdl.handle.net/20.500.12110/paper_03044165_v1860_n1_p129_Michelini
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_03044165_v1860_n1_p129_Michelini2023-06-08T15:29:54Z Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors Michelini, Flavia Mariana Bueno, Carlos Alberto Alche, Laura Edith Ramirez, Javier Alberto 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 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. Fil:Michelini, F.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Bueno, C.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Alché, L.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ramírez, J.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03044165_v1860_n1_p129_Michelini http://hdl.handle.net/20.500.12110/paper_03044165_v1860_n1_p129_Michelini
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 Michelini, Flavia Mariana Bueno, Carlos Alberto Alche, Laura Edith Ramirez, Javier Alberto Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
topic_facet	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
description	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.
author	Michelini, Flavia Mariana Bueno, Carlos Alberto Alche, Laura Edith Ramirez, Javier Alberto
author_facet	Michelini, Flavia Mariana Bueno, Carlos Alberto Alche, Laura Edith Ramirez, Javier Alberto
author_sort	Michelini, Flavia Mariana
title	Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
title_short	Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
title_full	Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
title_fullStr	Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
title_full_unstemmed	Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors
title_sort	synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit erk and akt signaling pathways without binding to glucocorticoid receptors
publishDate	2016
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_03044165_v1860_n1_p129_Michelini http://hdl.handle.net/20.500.12110/paper_03044165_v1860_n1_p129_Michelini
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_version_	1768544730159775744

Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors

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