Synthesis, immunosuppressive properties, mechanism of action and X-ray analysis of a new class of isoxazole derivatives
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In the search for potential therapeutics, isoxazole derivatives are still objects of interest. Previously described immunoregulatory properties of 5-amino-3-methyl-4-isoxazolecarboxylic acid (AC) benzylamides prompted us to synthesize a new class of compounds of immunotropic activity. A series of new compounds containing the isoxazole moiety were synthesized using Passerini three-component reaction. The effects on phytohemagglutinin A (PHA)-induced proliferation of human peripheral blood mononuclear cells (PBMC), production of tumor necrosis factor alpha (TNF α) in human whole blood cultures stimulated with lipopolysaccharide (LPS) and two-way mixed lymphocyte reaction (MLR) of PBMC, were investigated. Also, the effect of 1-(cyclohexylcarbamoyl)cyclohexyl 5-amino-3-methylisoxazole-4-carboxylate (PUB1) on the expression of signaling molecules associated with cell apoptosis in Jurkat cells was also determined. The results showed that the compounds inhibited to various degree mitogen-induced PBMC proliferation in a dose-dependent manner and TNF α production at 10 μg/ml. PUB1 compound, selected on the basis of its strongest antiproliferative activity, was also shown to inhibit MLR. The molecular data suggest that immunosuppressive action of PUB1 depended on induction of Fas and elevation of caspase 8 expression. In summary, we revealed immunosuppressive properties of a new class of isoxazoles and established the mechanism of action of a representative PUB1 compound.
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