Synthesis of carboxylated flavonoids as new leads for LTD 4 antagonists

Abstract

Summary A series of 3′- and 5′-carboxylated chalcones, 6- or 8-carboxylated flavones and 6-carboxylated flavanones, -flavanols and -flavans were prepared. The compounds were tested for their inhibitory activities against leukotriene D 4 (LTD 4 ) induced contraction of guinea-pig ileum. A new and convenient synthetic route to 3-acetyl-2-hydroxybenzoic acid ( 1d ), a key intermediate for the synthesis of 3′-carboxy-2′-hydroxychalcones and 8-carboxylated flavones, was developed. The activities of the tested compounds ranged from 0 to 63% inhibition at 10 −5 M drug concentration against a single challenge of 10 −8 M LTD 4 . Several compounds were tested in a radioligand binding assay against [ 3 H]LTD 4 on guinea-pig lung membrane. The quinoline-containing chalcone 12 and flavone 17 were found to exhibit significant but weak affinities for LTD 4 receptors with p K D -values of 4.95 and 4.83, respectively, and are interesting lead structures for the development of rigid LTD 4 antagonists. In contrast, the rest of the compounds tested in the binding assay did not show significant displacement of the radioligand, implying that for these compounds the functional activity is probably not caused by competitive antagonism at the LTD 4 receptor. The exact mechanism of the relaxant activity remains unclear.