Study On The Design, Synthesis And Antitumor Activity Of 4 - Aniline Quinazoline Fluorinated Derivatives

4-Anilinoquinazoline is a kind of small molecular inhibitors against epidermal growth factor receptor tyrosine kinase (EGFR-TK). In past decade, there are several 4-anninoquinazolines such as Gefitinib and Erlotinib have been approved by FDA for treatment tumors in clinic. The most studies on structural modification of 4-anlilinoquinazoline were focused on the chains at 6,7-positions and the substituents of 4-anline. However, there is a lack of investigation about the structure activity relationship on 2-position of the mentioned scaffold.In this research, three series of novel 2-floro-4-anlilinoquinazoline derivatives were designed, based on the X-Ray structure of EGFR complexed with Erlotinib (PDB code:IM17) and classic theories of medicinal chemistry. The aimed compounds, including 6,7-dimethoxy-,6,7-bis(2-methoxyethoxy)-and 6-acrylamide -2-floro-4-anlilinoquinazolines were obtained through the halogen exchange reactions from corresponding 2-chloro-4-anilinoquinazoine derivatives. In addition, we could also provide the synthetic methods and the precursors for preparation of 2-18F-4-anilinoquinazolines as PET tracers for tumor diagnosis.All of the 2-chloro-and 2-floro-4-anilinoquinazoines were screened against the tyrosine kinase of EGFR, mutated EGFR (T790M/L858R) and cell lines of A431, PC9 and A549 in vitro. The biological screening data indicated:1). Most of the compounds demonstrate EGFR inhibitory activities significantly.2). The efficacy of 2-floro-4-anilinoquinazolines were more superior comparing with the chloro-substituted ones.3).2-Floro-4-anilinoquinazolines showed most promising anti-tumor cell activities in vitro, which deserve further exploration as a new class of EGFR inhibitors.