SYNTHESIS OF CARBOXYLATED FLAVONOIDS AS NEW LEADS FOR LTD(4) ANTAGONISTS

A series of 3'- and 5'-carboxylated chalcones, 6- or 8-carboxylated fl avones and 6-carboxylated flavanones, -flavanols and -flavans were pre pared. The compounds were tested for their inhibitory activities again st 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'-hydroxycha lcones and 8-carboxylated flavones, was developed. The activities of t he tested compounds ranged from 0 to 63% inhibition at 10(-5) M drug c oncentration against a single challenge of 10(-8) M LTD(4). Several co mpounds were tested in a radioligand binding assay against [H-3]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 pK(D)-values of 4.95 and 4.83, respectively, and are interesting lead structures for the development of rigid LTD(4) a ntagonists. In contrast, the rest of the compounds tested in the bindi ng assay did not show significant displacement of the radioligand, imp lying that for these compounds the functional activity is probably not caused by competitive antagonism at the LTD(4) receptor. The exact me chanism of the relaxant activity remains unclear.