Abstract
A series of variously substituted furochromenes, hemiacetals 2, acetals 3, and rearranged compounds 4, were synthesized from variously substituted 4-hydroxycoumarins and evaluated in several in vitro assays, inhibition of mast cell degranulation induced by the activation of Fce receptor type I or calcium ionophore and leukotriene B4 (LTB4) inhibition. The most active derivatives, 3p and 4p (8-iso-propyl substitution in coumarin ring) and 3r (5-methyl-8-chloro substitution), showed significant inhibition of mast cell degranulation (Fctriggered) and LTB4, and exhibited significant local anti-inflammatory activity in PMA induced ear edema in CD1 mice, with potency equal (compounds 3p and 4p) or better (compound 3r) in comparison with zileuton, a reference drug used. It might be a promising direction for developing novel drugs as potential agents for the treatment of allergies and other inflammatory diseases.(doi: 10.5562/cca2240)
Highlights
Coumarins represent an important class of oxygenated heterocycles
Intensive investigation on the molecular level of action of these compounds showed that they prevent reduction of vitamin K epoxide to active vitamin K inhibiting the biosynthesis of protrombin and other clothing factors.[9]
It was shown that selinidin modulates Fcε receptor type I mediated signaling it does not prevent immunoglobulin E (IgE)-Fcε receptor type I binding and cell surface Fcε receptor type I expression. These results suggest that selinidin suppresses IgE-mediated mast cell activation by inhibiting signal transduction pathways through Fcε receptor type I
Summary
Coumarins represent an important class of oxygenated heterocycles. Since many of them, both naturally occurring and synthetic, possess diverse array of biological activities, they are of potential pharmaceutical interest. Anti-inflammatory activity of prepared compounds was examined on the basis of in vitro tests, inhibition of mast cell (RBL-2H3 cell line of rat basophilic leukaemia) degranulation induced by the activation of Fcε receptor type I. Discovery of new generation of compounds which would inhibit mast cell degranulation as well as prevent synthesis of leukotrienes potentially provides a therapeutic approach for treatment of allergies and other inflammatory diseases. After cooling to the room temperature the product was collected by filtration and washed with acetic acid and diethyl ether, affording furochromen derivatives 4 as pure compounds. Dilutions of tested compounds are placed on cells, whereas for positive and negative controls only DMEM medium without phenol red are used and left in culturing conditions for 30 minutes. All procedures on animals were performed in accordance with (a) the EEC Council Directive 86 / 609 of 24th November 1986 on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes; and (b) Statute of Republic Croatia, Animal Welfare Law, NN 135 of 13th December 2006
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