Human neutrophil elastase inhibitory dihydrobenzoxanthones and alkylated flavones from the Artocarpus elasticus root barks

초록

Neutrophil elastases are deposited in azurophilic granules interspace of neutrophils and tightly associated with inflammatory ailments. The root barks ofArtocarpus elasticushad a strong inhibitory potential against human neutrophil elastase (HNE). The responsible components for HNE inhibition were confirmed as alkylated flavones (2-4, IC50 = 14.8 similar to 18.1 mu M) and dihydrobenzoxanthones (5-8, IC50 = 9.8 similar to 28.7 mu M). Alkyl groups on flavone were found to be crucial functionalities for HNE inhibition. For instance, alkylated flavone2(IC50 = 14.8 mu M) was 20-fold potent than mother compound norartocarpetin (1, IC50 > 300 mu M). The kinetic analysis showed that alkylated flavones (2-4) were noncompetitive inhibition, while dihydrobenzoxanthones (5-8) were a mixed type I (K-I < K-IS) inhibitors, which usually binds with free enzyme better than to complex of enzyme-substrate. Inhibitors and HNE enzyme binding affinities were examined by fluorescence quenching effect. In the result, the binding affinity constants (K-SV) had a significant correlation with inhibitory potencies (IC50).

키워드