Title:Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy
Functionalized Pteridine Derivatives as EGFR Inhibitors
Volume: 18
Issue: 3
Author(s): Jin Lin, Zemin Zhang, Xiongqiang Lin, Zhendong Chen, Tian Luc, Daijun Zha, Jian Wang, Xiuzhi Xu and Zhulai Li*
Affiliation:
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fujian Medical University, Fuzhou, China
- Department of Medicinal Chemistry, School of Pharmacy, Fujian Medical University, Fuzhou, China
Keywords:
Pteridine, derivatives, EGFR, inhibitor, 2, 2, 2-trifluoroethoxy, antitumor activity.
Abstract: 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 the
anticancer therapy.
Objective: This work aimed at designing and synthesizing 6-2,2,2-trifluoroethoxy functionalized
pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor.
Methods: 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. The molecular docking model displayed
a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which
lied 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 antiproliferative
activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway,
providing a new perspective for the modification of pteridine-based derivatives as EGFR inhibitor.
