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Molecules 2018, 23(7), 1545; https://doi.org/10.3390/molecules23071545

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

1
Faculty of Pharmacy, Department of Organic Chemistry, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
2
Faculty of Medicine, Histology and Embryology Division, Wroclaw Medical University, Chalubinskiego 6a, 50-368 Wroclaw, Poland
3
Institute of Immunology and Experimental Therapy, Laboratory of Immunobiology, Weigla 12, 53-114 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Received: 11 June 2018 / Revised: 21 June 2018 / Accepted: 26 June 2018 / Published: 26 June 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

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 (MM1MM10) 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. View Full-Text
Keywords: isoxazole; PBMC; proliferation; TNF α; apoptosis; jurkat cells isoxazole; PBMC; proliferation; TNF α; apoptosis; jurkat cells
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Mączyński, M.; Borska, S.; Mieszała, K.; Kocięba, M.; Zaczyńska, E.; Kochanowska, I.; Zimecki, M. Synthesis, Immunosuppressive Properties, and Mechanism of Action of a New Isoxazole Derivative. Molecules 2018, 23, 1545.

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