title: Synthesis and antiproliferative properties of 4-aminoquinazoline derivatives as inhibitors of EGF receptor-associated tyrosine kinase activity.
abstract: The mitogenic action of EGF is mediated by ligand-induced autophosphorylation of the EGF receptor (EGF-R), which is commonly overexpressed in numerous human cancers. Inhibitors of receptor tyrosine kinase (RTK) activity could therefore be considered as effective potential antitumor agents. For this purpose, 4-aminoquinazoline derivatives were prepared and evaluated for their ability to inhibit RTK activity and the autophosphorylation of EGF-R. In addition, these compounds were tested on A431 cell growth to estimate their antiproliferative effect. The results showed that the substituent at the 4-position of the quinazoline ring must be an aromatic amine carrying small lipophilic electron-withdrawing groups on the 3- (or 2-) position of the phenyl ring. This aromatic moiety might be far from the quinazoline provided that the linking group is conformationally restricted, such as with piperazine. Hydrophilic and non-aromatic substituents such as morpholine gave completely inactive compounds. Introduction of a bulk at the 2-position of the quinazoline ring in 2,4-diaminoquinazolines or tricyclic compounds led to inactive products. This study reports additional structure-activity relationships of a well-characterized series to develop new inhibitors of EGF-R-associated tyrosine kinase activity.
authors.affiliation: Institut de Chimie Pharmaceutique de Lille, Faculté des Sciences, Pharmaceutiques et Biologiques, France.
authors.forename: E
authors.initials: E
authors.lastname: Bouey-Bencteux
authors.forename: C
authors.initials: C
authors.lastname: Loison
authors.forename: N
authors.initials: N
authors.lastname: Pommery
authors.forename: R
authors.initials: R
authors.lastname: Houssin
authors.forename: J P
authors.initials: JP
authors.lastname: Hénichart
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases