Design, Synthesis And Anticancer Activity Evaluation Of Epidermal Growth Factor Receptor Inhibitors With Novel Fluorinated Pteridine Structures

The molecular biology and genetic engineering reveal that tyrosine kinases have the colse relationship with the occurrence and development of tumor,and its overexpression and tumor cells proliferation are closely related.Therefore,it can be used for treating tumors by inhibiting the activity of a protein tyrosine kinase.Currently,quinazoline is one of the most widespread scaffolds which are appeared in anticancer drugs as the protein tyrosine kinase inhibitor.Many fluorine-containing drugs have been widely used in clinical practice.Introducing fluorine atoms and fluorine-containing groups into drugs can improve the clinical efficacy of drugs and reduce their side effects.Hence,this paper optimizes the experimental route and reaction conditions,designed and synthesized a series of novel fluorinated tyrosine kinase inhibitors through the introduction of fluorine atoms.This dissertation mainly involves the synthesis of target compounds,evaluation of the in vitro bioactivity as well as molecular simulation and docking by computer-aided drug design.1.A series of novel fluorinated pteridine compounds were synthesized with 3-aminopyrazine-2-formic acid as a raw material by aminolysis,bromination,cyclization,alkoxylation,chlorination and ammoniationreaction of chlorinated product,total yield was 20%.The as-prepared compounds were characterized in detail by organic spectroscopy,such as ¹H-NMR,¹³C-NMR,¹⁹F-NMR as well as mass spectrometry analysis,respectively.The results indicated that all the target compounds were successfully synthesized and could be used for the further bioactivity evaluation.2.We next set out to test the anticancer activities.Three typical specie s,such as the human colon cancer cell line HCT-116,the human non-small cell lung cancer cell line A549,and the human gastric cancer cell line SGC-7901 were selected.The in vitro antitumor activity of the target compound was determined by the MTT method.The results showed that the target compound had a certain inhibitory effect on the three cell lines.Among of them,7b-3?4-?4-fluoro-2-nitrophenylamine?-6-trifluoroethoxypteridine?had a good activity against human non-small cell lung cancer cell line A549 with an IC50 of 18.35?g/mL.3.Molecular simulation and docking by computer-aided drug design,in the molecular simulation docking,SYBYL-X 1.3 was combined with PyMol software to molecularly dock the 29 target compounds,and the score of 7b-3 was the highest in the score.Above results indicated that the score results were consistent with the experimental results of anti-tumor activity.