Synthesis and evaluation of tricyclic quinazoline derivatives as egfr inhibitors

In the last few years, among various suitable biological targets for cancer treatment, special attention was given to the inhibition of tyrosine kinase, leading the scientific community to identify several biologically interesting classes of compounds. In particular 4-anilinoquinazoline derivatives have shown highly specific and potent antitumoral activity, acting as ATP-competitive antagonist toward EGFR. This inhibition blocks the proliferative cascade regulated by the receptorial enzyme, and so induces apoptosis. We have synthesized, with a novel synthetic strategy, several fused tricyclic quinazoline derivatives, with the aim to evaluate their biological activity and to reach further information on the structure-activity relationship for this class of compounds. Structures of synthesized compounds are summarized in the figure below. The effects on cell growth induced by all the synthesized compounds were evaluated in both human squamous carcinoma cells (A431) and mouse embryonic fibroblasts (NIH3T3) expressing EGFR at various levels. Biological data were compared with those obtained using PD153035.