title: Synthesis and structure-activity studies of a series of [(hydroxybenzyl)amino]salicylates as inhibitors of EGF receptor-associated tyrosine kinase activity.
abstract: The synthesis and structure-activity relationships of a series of [(hydroxybenzylidene)amino]salicylates and a series of [(hydroxybenzyl)amino]salicylates as inhibitors of EGF receptor-associated tyrosine kinase activity are described. Their inhibitory potency was evaluated in vitro using ER 22 cell membranes (CCL 39 cells transfected with EGF receptor) as an enzyme source and the tridecapeptide RRSrc (RRLIEDAEYAARG) as substrate. Their cellular activity was measured by inhibition of the EGF-stimulated DNA synthesis of ER 22 cells. Chemical modifications were made to analyze the role of the different substituents. The amino series was found to be more active than the imino series. The hydroquinone 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 techniques provides further evidence in support of the hypothesis that the important reduced linking chain, CH2NH, allows the correct positioning of the 2,5-dihydroxybenzyl ring, possibly in a cis-like conformational arrangement.
authors.affiliation: UFR des Sciences Pharmaceutiques et Biologiques Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS URA D 1500, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Boiziau
authors.forename: F
authors.initials: F
authors.lastname: Parker
authors.forename: R
authors.initials: R
authors.lastname: Maroun
authors.forename: B
authors.initials: B
authors.lastname: Tocque
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
authors.forename: C
authors.initials: C
authors.lastname: Garbay-Jaureguiberry
mesh_terms: D000636:Aminosalicylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000636:Aminosalicylic Acids; D066246:ErbB Receptors