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Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative

This work describes the synthesis of a new series of isoxazole derivatives, their immunosuppressive properties, and the mechanism of action of a representative compound. A new series of N′-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM1–MM10) was synthesized in reac...

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Autores principales: Mączyński, Marcin, Borska, Sylwia, Mieszała, Katarzyna, Kocięba, Maja, Zaczyńska, Ewa, Kochanowska, Iwona, Zimecki, Michał
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099534/
https://www.ncbi.nlm.nih.gov/pubmed/29949951
http://dx.doi.org/10.3390/molecules23071545
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author Mączyński, Marcin
Borska, Sylwia
Mieszała, Katarzyna
Kocięba, Maja
Zaczyńska, Ewa
Kochanowska, Iwona
Zimecki, Michał
author_facet Mączyński, Marcin
Borska, Sylwia
Mieszała, Katarzyna
Kocięba, Maja
Zaczyńska, Ewa
Kochanowska, Iwona
Zimecki, Michał
author_sort Mączyński, Marcin
collection PubMed
description This work describes the synthesis of a new series of isoxazole derivatives, their immunosuppressive properties, and the mechanism of action of a representative compound. A new series of N′-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM1–MM10) was synthesized in reaction of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with relevant carbonyl compounds. The isoxazole derivatives were tested in several in vitro models using human cells. The compounds inhibited phytohemagglutinin A (PHA)-induced proliferation of peripheral blood mononuclear cells (PBMCs) to various degrees. The toxicity of the compounds with regard to a reference A549 cell line was also differential. 5-amino-N′-(2,4-dihydroxyphenyl)methylidene-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM3) compound was selected for further investigation because of its lack of toxicity and because it had the strongest antiproliferative activity. The compound was shown to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF α) production in human whole blood cell cultures. In the model of Jurkat cells, MM3 elicited strong increases in the expression of caspases, Fas, and NF-κB1, indicating that a proapoptotic action may account for its immunosuppressive action in the studied models.
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spelling pubmed-60995342018-11-13 Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative Mączyński, Marcin Borska, Sylwia Mieszała, Katarzyna Kocięba, Maja Zaczyńska, Ewa Kochanowska, Iwona Zimecki, Michał Molecules Article This work describes the synthesis of a new series of isoxazole derivatives, their immunosuppressive properties, and the mechanism of action of a representative compound. A new series of N′-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM1–MM10) was synthesized in reaction of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with relevant carbonyl compounds. The isoxazole derivatives were tested in several in vitro models using human cells. The compounds inhibited phytohemagglutinin A (PHA)-induced proliferation of peripheral blood mononuclear cells (PBMCs) to various degrees. The toxicity of the compounds with regard to a reference A549 cell line was also differential. 5-amino-N′-(2,4-dihydroxyphenyl)methylidene-N,3-dimethyl-1,2-oxazole-4-carbohydrazide (MM3) compound was selected for further investigation because of its lack of toxicity and because it had the strongest antiproliferative activity. The compound was shown to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF α) production in human whole blood cell cultures. In the model of Jurkat cells, MM3 elicited strong increases in the expression of caspases, Fas, and NF-κB1, indicating that a proapoptotic action may account for its immunosuppressive action in the studied models. MDPI 2018-06-26 /pmc/articles/PMC6099534/ /pubmed/29949951 http://dx.doi.org/10.3390/molecules23071545 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mączyński, Marcin
Borska, Sylwia
Mieszała, Katarzyna
Kocięba, Maja
Zaczyńska, Ewa
Kochanowska, Iwona
Zimecki, Michał
Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative
title Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative
title_full Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative
title_fullStr Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative
title_full_unstemmed Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative
title_short Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative
title_sort synthesis, immunosuppressive properties, and mechanism of action of a new isoxazole derivative
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099534/
https://www.ncbi.nlm.nih.gov/pubmed/29949951
http://dx.doi.org/10.3390/molecules23071545
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