Design,Synthesis And Anticancer Evaluation Of 2,6-Disubstituting Purine Derivatives

In this paper,the intermediate 2-chloro-6-fatty amino purine derivatives were synthesized by 2,6-dichloropurine and diamine which were used as starting materials according to the principle of N-alkyl reaction.Then it reacted with aniline to synthesize 2-aniline-6-fat amino purine derivatives under the effect of Lewis acid.After dissolved by H₂O:CH₃CN=2:3,the two derivatives were reacted respectively with 4-nitrophenyl chloroformate to synthesize active esters.The temperature was 0℃and Na HCO₃was used as bound acid agent.Lastly,2-chlorine/aniline 6-fatty amine purine hydroxamic acid derivatives were synthesized by activity esters and hydroxylamine hydrochloride.The C-2 and C-6 of purine were modificated,a series of 2,6-diamine purine derivatives were synthesized and we studied the molecular docking of CDK2 with some target compounds.Synthesis of the derivatives were determined their anti-tumor activities in vitro to explore their anti-tumor effect against human gastric carcinoma cell line SGC-7901.Furthermore,we have preliminarily analyzed the structure and activity relation of target compounds basing on their anti-tumor activities.Furthermore,according to the situation of such compounds on the inhibition of tumor cells and molecular docking,the structure-activity relationship was also preliminarily analyzed.This paper mainly includes the following aspects:Firstly,the research progress of purine derivatives,the mechanism of purine antitumor medicine,clinical applications.The research progress of 2,6-diamine replace purine derivatives,the application of hydroxamic acid.Secondly,Computer aided drug design,the target compounds with CDK2（PDB id-2C6O）of molecular docking studies,the reaction between target receptor,characteristics force of hydrogen bonding,advantages of structure are discussed.Thirdly,according to the literature,the design and synthetic route of purine derivatives,20 target compounds were synthesized.The chemical structures of all compounds were confirmed by IR,MS,¹H-NMR,¹³C-NMR.Fourthly,we have evaluated anti-tumor activities in vitro to explore their anti-tumor effect against human gastric carcinoma cell line SGC-7901 by MTT.The anti-tumor activities in vitro cells demonstrate that lots of target compounds show higher activity than Positive contrast 5-FU,and some of them show higher activity than 5-FU(SGC-7901,IC₅₀:149.54μM),they are 5j(IC₅₀:125.32μM)、8n(IC₅₀:127.76μM)、4e(IC₅₀:129.75μM)、10l(IC₅₀:141.64μM)、7g(IC₅₀:145.50μM).