title: 5-Amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives with in vitro immunomodulatory activities.
abstract: Isoxazoles are an important class of compounds of potential therapeutic value. The aim of this study was to determine immunotropic effects of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives on spontaneous and mitogen-induced lymphocyte proliferation in young and old mice, cytokine production by peritoneal cells as well as possible mechanism of action in a model of Jurkat cells. Three-month-old and 13-month-old BALB/c mice were used as donors of the cells from a thymus, a spleen, mesenteric lymph nodes, and a peritoneal cavity. Spontaneous and concanavalin A or lipopolysaccharide (LPS)-induced cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric method. IL-1β and TNF-α production induced by LPS in macrophage-enriched peritoneal cell cultures was measured by enzyme-linked immunoassay. 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide, 01K (4-phenyl-1-(5-amino-3-methylisoxazole-4-carbonyl)-thiosemicarbazide), and 06K (4-(4-chlorophenyl)-1-(5-amino-3-methylisoxazole-4-carbonyl)-thiosemicarbazide) exhibited regulatory activity in the proliferation tests. Prevailing stimulatory activity of the hydrazide and inhibitory activity of 01K and 06K was observed. Those effects were connected with different influence of the compounds on signaling proteins expression in Jurkat cells. The regulatory effects of the compounds on IL-1β production were more profound than those on TNF-α. Differences in the compound activity in young versus old mice were mainly restricted to 01K. Immunosuppressive isoxazole leflunomide and a stimulatory RM-11 (1,7-dimethyl-8-oxo-1,2H-isoxazole [5,4-e]triazepine) were applied as reference drugs.
authors: Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Wrocław, Poland.
authors: Angelika
authors: A
authors: Drynda
authors: Department of Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Wrocław, Poland.
authors: Bożena
authors: B
authors: Obmińska-Mrukowicz
authors: Laboratory of Immunobiology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
authors: Ewa
authors: E
authors: Zaczyńska
authors: Laboratory of Immunobiology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
authors: Michał
authors: M
authors: Zimecki
authors: Laboratory of Immunobiology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.
authors: Iwona
authors: I
authors: Kochanowska
authors: Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Wrocław, Poland.
authors: Stanisław
authors: S
authors: Ryng
authors: Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Wrocław, Poland.
authors: Marcin
authors: M
authors: Mączyński
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology; D019169:Jurkat Cells; D000077339:Leflunomide; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D007555:Isoxazoles; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D053453:Caspase 9; D000077339:Leflunomide
keywords: 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide; IL-1β; TNF-α; isoxazoles; lymphocyte proliferation