Study On Synthesis And Antitumor Activities Of New Type Of Small Molecules Pteridine

Based on previous study,this thesis analyzes crystal structure formed by tyrosine kinase inhibitors and receptor proteins,targets receptor tyrosine kinases,choses Gefitinib and Erlotinib as lead compound and uses bioiosterism principles.Some small molecule compounds that have high anti-tumor activity,low toxic and side effects and good tagetability.The content involves four aspects:(1)new chemical entity synthesis:a series of new 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.(2)Using Organic Spectrum Techniques(MS,1H-NMR,13C-NMR),the structure of target compounds was confirmed.(3)The synthesis of intermediate 3-amino-6-bromopyrazine-2-carboxamide,6-bromopyazine-4(3H)-pteridinone and 6-alkoxy-4-chloropterdine was detailed analyzed.The by-product that was produced in the process of synthesizing 4-(aromatic amino)-6-alkoxy pteridine was deeply discussed and its structure was identified.(4)The antineoplastic activity of new pteridine compounds on the human non-small cell lung cancer cell A549,human gastric carcinoma cells HGC-27 and Human acute myeloid leukemia cells KG1 a was evaluated by MTT detection method.The result indicates:(1)Synthesized compounds,4-(aromatic amino)-6-alkoxy pteridine,confirmed by spectrum analysis,was not found in other reports and was new chemical entity.(2)The chlorinated intermediates reacted with aryl amine to give the desired corresponding products under microwave irradiation.It has an advantage compared to the conventional method.(3)The series of pteridine compounds have higher inhibition activity towards human non-small cell hung cancer A549 than other cells.4-(2-chloro-5-nitroamino)-6-methoxyethoxy pteridine(7a-2)showed the strongest biological activity in the compounds.The IC50 values of 7a-2 on A549 is 4.35 μg/mL,which is closer to the positive drug Gefitinib.The anti-tumor activity of 7b-2 showed high data in all three cells.The IC50 value of 7b-2 on three cells are all approach the level of Gefitinib.