SYNTHESIS AND STRUCTURE-ACTIVITY STUDIES OF A SERIES OF [(HYDROXYBENZYL)AMINO]SALICYLATES AS INHIBITORS OF EGF RECEPTOR-ASSOCIATED TYROSINEKINASE-ACTIVITY

The synthesis and structure-activity relationships of a series of [(hy droxybenzylidene)amino] salicylates and a series of [(hydroxybenzyl)am ino] salicylates as inhibitors of EGF receptor-associated tyrosine kin ase activity are described. Their inhibitory potency was evaluated in vitro using ER 22 cell membranes (CCL 39 cells transfected with EGF re ceptor) as an enzyme source and the tridecapeptide RRSrc (RRLIEDAEYAAR G) as substrate. Their cellular activity was measured by inhibition of the EGF-stimulated DNA synthesis of ER 22 cells. Chemical modificatio ns were made to analyze the role of the different substituents. The am ino series was found to be more active than the imino series. The hydr oquinone moiety appears to be essential for tyrosine kinase inhibitory activity in the series of 5-[(2,5-dihydroxybenzyl)amino]salicylates. Comparison of the imino and amino series by molecular modeling techniq ues provides further evidence in support of the hypothesis that the im portant reduced linking chain, CH2NH, allows the correct positioning o f the 2,5-dihydroxybenzyl ring, possibly in a cis-like conformational arrangement.