Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors.

Background Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR, which are attractive targets for anticancer therapy. Objective This work aimed to design and synthesize 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor. Method Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17]. Results The compound 7m, with IC50 values of 27.40 μM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 μM. Molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lay at the ATP binding site of EGFR kinase domain. Conclusion The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the anti-proliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for modification on pteridine-based derivatives as EGFR inhibitor.