In situ screening of 3-arylcoumarin derivatives reveals new inhibitors of mast cell degranulation.

Due to the severity and high prevalence of allergic diseases, there is growing interest in the development of inhibitors of such conditions. 3-Arylcoumarin derivatives emerge as promising compounds for the treatment of allergic disorders, in particular due to their close structural similarity to flavonoids, whose anti-allergic activity has been extensively reported. The aim of this work was to perform a screening of a set of 3-arylcoumarins as potential inhibitors of mast cell degranulation, a key event for the development of allergic reactions. For that purpose, it was utilized a biosensor model based on mast cells, whose in vitro assay allows for such screening, in a high throughput fashion, and also permits bringing to attention some coumarin structural features that are important for their biological activity. The mast cell-based biosensor was shown to discriminate, with high sensitivity and reproducibility, between coumarins that did not affect or caused different degrees of inhibition of degranulation. Among active coumarins, some substituents could be accounted for their inhibitory activity, such as the hydroxylation of positions 6 and 2' of 3-phenylcoumarins, in addition to catechol, amino and thiophene moieties. In summary, 3-arylcoumarins could be suggested as potential candidates for the development of new anti-allergic drugs.

In vitro anti-allergic activity of the fungal metabolite pyridovericin.

Mast cells play a critical role during the development of an allergic response. Upon activation by an antigen and IgE, via FcεRI receptors, mast cells release histamine and other mediators that initiate and propagate immediate hypersensitivity reactions. Mast cells also secrete cytokines that regulate the immune responses. In this way, inhibitors of mast cell activity could work as promising therapeutics for allergic disorders. In the present work, we investigated the capacity of pyridovericin, a natural product isolated from the entomopathogenic fungus Beauveria bassiana, to inhibit mast cell degranulation and cytokine secretion. It was found that pyridovericin strongly decreased the release of ß-hexosaminidase, a marker for mast cell degranulation, when mast cells were stimulated by both FcεRI-dependent and independent pathways. In addition, pyridovericin strongly abrogated secretion of interleukin-4. Pyridovericin-mediated suppression of stimulated increase in intracellular Ca(2+) levels, a crucial signal for mounting of both degranulation and cytokine production responses, was ascribed as one of the inhibition targets of pyridovericin. Those initial studies identify pyridovericin as a potential new candidate for the development of new anti-allergic drugs.