Synthesis and evaluation of erlotinib analogues: exploiting ring closure

Identification of novel targets critical for cancer growth and progression, and development of inhibitory strategies to hit these targets are fundamental to reach significant advances in cancer treatment. To date, scientific community efforts directed to small organic compound development for anticancer therapy have allowed to identify several biologically interesting classes of compounds. In the last few years, particular attention was given to 4-anilinoquinazoline derivatives, such as Erlotinib or PD153035 for their highly specific and potent antitumoral activity as tyrosine kinase inhibitor. These compounds act as ATP-competitive antagonist towards several receptorial enzyme, such as EGFR, blocking the proliferative cascade, and so inducing apoptosis. The therapeutic potential of these quinazoline derivatives is actually under extensive investigation in several clinical trials. Synthesis of these derivatives is often limited by the lack of commercially available starting products. To going over this drawback of the already known synthetic routes, our research group has developed a novel synthetic strategy, which have also been improved by microwave-assisted technique. Starting from QSAR, docking and crystallographic literature data, we have decided to investigate how a condensed dioxygenated ring might influence the biological activity of several 4-anilinoquinazoline derivatives. 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. EGFR tyrosine kinase activity was also assessed by measuring the phosphorilation of a synthetic peptide substrate after treatment of A431 cells. Biological data were compared with those obtained using PD153035.