Design, Synthesis And Anti-tumor Activity Evaluation Of New PI3K? Inhibitors

Objective:Phosphatidylinositol-3 kinase(PI3K)is involved in multiple signal transduction pathways.Three types of PI3 Ks have been identified in mammals,in which class I PI3 Ks are involved in the etiology and maintenance of various diseases.They are important targets for tumor treatment.Class I PI3 Ks are further divided into four subtypes:???????.This paper aims to design and synthesize novel and high active PI3K? inhibitors based on the reported three-dimensional crystal structure of the protein of PI3 K productions and the structural characteristics of excellent PI3K?inhibitors entering the clinic.Methods:First,the PI3 K scaffold three-dimensional crystal structure 3P2 B was selected as the virtual docking receptor in the Protein Data Bank database,and processed by SYBYL.The virtual compound library "Maybridge Screening Collection" was searched and four compounds with high score and typical inhibitory activity of PI3K?were selected.The scifinder database was investigated,and the compound Med-4,which has few patent structure of similar compounds,was selected as the lead compound for further research.The thiazolpyridinium heavy heterocyclic,morpholine ring and hydrogen-bonded donors at the para-position of benzene ring in the side chain are important active structures,which are retained.The structural characteristics of dominant PI3K? inhibitors were summarized,the urea side chain structure and a morpholine ring were added,and 9 derivatives were obtained.The compounds in this series were synthesized as the targets,and the synthesis route was optimized.The synthesized compounds were characterized by MS and NMR.The antitumor activity of nine compounds was evaluated by using Med-4 as positive control.Results:In this study,six new inhibitors were synthesized,in which the inhibitory activity of compounds 1-(4-(2-((2S,6R)-2,6-dimethylmorpholine)-7-morpholine thiazole[5,4-b]pyridine-5-yl)phenyl)-3-ethyl urea and1-cyclopropyl-3-(4-(2-((2S,6R)-2,6-dimethylmorpholine)-7-morpholine thiazole[5,4-b] pyridine-5-phenyl)urea on MCF7 cell lines reached 2.78 mm and 1.464 mm,the enzyme inhibitory activity of PI3K? reached 50.4 n M and 37.4 n M,respectively,both are higher than the activity values of the lead compound Med-4.In this study,we obtained the preliminary structure-activity relationship of these compounds.In the next step,we will further modify the structure of PI3K? inhibitors with higher activity on the basis of preserving the dominant conformation in the obtained compounds.