Marcin Mączyński1, Jolanta Artym2, Maja Kocięba2, Iwona Kochanowska2, Stanisław Ryng3, Michał Zimecki2. 1. Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Wrocław, Poland. Electronic address: marcin.maczynski@umed.wroc.pl. 2. Laboratory of Immunobiology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland. 3. Department of Organic Chemistry, Faculty of Pharmacy, Wrocław Medical University, Wrocław, Poland.
Abstract
BACKGROUND: A series of new isoxazole derivatives of expected immunosuppressive activities was synthesized. Following in vitro screening in the human cell models, the activity of MZO-2 compound (ethyl N-{4-[(2,4-dimethoxybenzyl)carbamoyl]-3-methylisoxazol-5-yl}acetimidate) in mouse in vivo models was evaluated. METHODS: In vitro tests included evaluation of: peripheral blood mononuclear cells (PBMC) viability, phytohemagglutinin (PHA)-induced PBMC proliferation and lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF α) production in whole blood cell cultures. MZO-2 was studied in mice for its effects on: humoral immune response to sheep erythrocytes (SRBC), delayed type hypersensitivity (DTH) to ovalbumin (OVA), contact sensitivity to oxazolone and carrageenan-induced foot pad edema. In addition, the effect of MZO-2 on expression of caspases in Jurkat cells was determined. RESULTS: The studied compounds exhibited differential, dose-dependent effects to suppress PHA-induced PBMC proliferation and a weak property to suppress LPS-induced production of TNF α. MZO-2 had no effect on the induction phase of the humoral immune response to SRBC in vitro and in vivo, but moderately suppressed the induction phase of DTH to OVA. Its inhibitory effect on carrageenan-induced paw inflammation was potent. Likewise, MZO-2, applied in ointment, was very effective in reducing ear edema and number of lymphocytes in draining lymph nodes of mice sensitized to oxazolone, comparably to tacrolimus, the reference drug. The expression of caspases 3, 8 and 9 in Jurkat cells was inhibited by the compound. CONCLUSION: MZO-2, applied systemically or locally, may serve as a potential drug for amelioration of inflammatory processes.
BACKGROUND: A series of new isoxazole derivatives of expected immunosuppressive activities was synthesized. Following in vitro screening in the human cell models, the activity of MZO-2 compound (ethyl N-{4-[(2,4-dimethoxybenzyl)carbamoyl]-3-methylisoxazol-5-yl}acetimidate) in mouse in vivo models was evaluated. METHODS: In vitro tests included evaluation of: peripheral blood mononuclear cells (PBMC) viability, phytohemagglutinin (PHA)-induced PBMC proliferation and lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF α) production in whole blood cell cultures. MZO-2 was studied in mice for its effects on: humoral immune response to sheep erythrocytes (SRBC), delayed type hypersensitivity (DTH) to ovalbumin (OVA), contact sensitivity to oxazolone and carrageenan-induced foot pad edema. In addition, the effect of MZO-2 on expression of caspases in Jurkat cells was determined. RESULTS: The studied compounds exhibited differential, dose-dependent effects to suppress PHA-induced PBMC proliferation and a weak property to suppress LPS-induced production of TNF α. MZO-2 had no effect on the induction phase of the humoral immune response to SRBC in vitro and in vivo, but moderately suppressed the induction phase of DTH to OVA. Its inhibitory effect on carrageenan-induced paw inflammation was potent. Likewise, MZO-2, applied in ointment, was very effective in reducing ear edema and number of lymphocytes in draining lymph nodes of mice sensitized to oxazolone, comparably to tacrolimus, the reference drug. The expression of caspases 3, 8 and 9 in Jurkat cells was inhibited by the compound. CONCLUSION:MZO-2, applied systemically or locally, may serve as a potential drug for amelioration of inflammatory processes.
Authors: Marcin Mączyński; Andrzej Regiec; Aleksandra Sochacka-Ćwikła; Iwona Kochanowska; Maja Kocięba; Ewa Zaczyńska; Jolanta Artym; Wojciech Kałas; Michał Zimecki Journal: Pharmaceuticals (Basel) Date: 2021-05-15
Authors: Aleksandra Sochacka-Ćwikła; Andrzej Regiec; Michał Zimecki; Jolanta Artym; Ewa Zaczyńska; Maja Kocięba; Iwona Kochanowska; Iwona Bryndal; Anna Pyra; Marcin Mączyński Journal: Molecules Date: 2020-08-04 Impact factor: 4.411