Synthesis and antiproliferative properties of 4-aminoquinazoline derivatives as inhibitors of EGF receptor-associated tyrosine kinase activity

The mitogenic action of EGF is mediated by ligand-induced autophosphorylati on 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 p urpose, 4-aminoquinazoline derivatives were prepared and evaluated for thei r 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 ph enyl ring. This aromatic moiety might be far from the quinazoline provided that the linking group is conformationally restricted, such as with piperaz ine. Hydrophilic and non-aromatic substituents such as morpholine gave comp letely inactive compounds. Introduction of a bulk at the 2-position of the quinazoline ring in 2,4-diaminoquinazolines or tricyclic compounds led to i nactive products. This study reports additional structure-activity relation ships of a well-characterized series to develop new inhibitors of EGF-R-ass ociated tyrosine kinase activity.