Design,Synthesis And Evaluation Of Novel Phosphatidylinositol 3-Kinases Inhibitors

Objective:At present,most of the anticancer drugs used in clinic belong to cytotoxic drugs.Cytotoxic drugs can not only play an anti-tumor role,but also damage other normal cells,resulting in nausea,vomiting,alopecia,bone marrow suppression and other serious side effects.Therefore,researchers are interested in developing novel molecular targeted anti-cancer drugs with high selectivity and low toxicity.PI3K,as an important target of anti-cancer drug research and development,has attracted great attention.In this paper,novel PI3K inhibitors were found through computer-aided drug design,chemical synthesis and activity screening,which laid a foundation for the development of anticancer drugs.Methods:1.The structure of ZSTK474,a broad spectrum PI3K inhibitor at the stage of clinical research,was reconstructed by using isosterism and ring expansion/contraction strategies.Then a series of compounds were docked by modification.The docking scores and ligand-protein complex binding modes were analyzed.These compounds,which had better docking results with four subtypes were selected.2.Based on the result of the first part,these compounds were synthesized and their structures were confirmed by ¹H-NMR,¹³C-NMR and Mass spectrum.3.MTT assay was used to detect the proliferation inhibition activity of the synthesized compounds on PC3 cells,and the IC₅₀ value of the drugs was calculated.4.Through virtual screening and Glide SP?standard precision?of Zinc database,these compounds with better docking results than the original ligands were selected for further ADMET prediction and molecular dynamics simulation.Finally,PI3K?/?inhibitors with better docking results,less toxicity and good pharmacokinetic characteristics were obtained.5.The Ligand Expo database was screened by means of virtual screening,Glide SP?standard precision?,ADMET prediction and molecular dynamics simulation.Finally,potential PI3K?/?inhibitors were obtained.6.Structural modification of PI3K?inhibitor Idelalisib was carried out by using combination principle,isosterism and scaffold hopping,and then the modified compounds were docked.Compounds with better docking scores and binding modes than Idelalisib were selected for further ADMET prediction and molecular dynamics simulation experiments.Finally,potential PI3K?inhibitors were obtained.Results:1.ZSTK474 was modified using the strategies of isosterism and ring expansion/contraction.Then 5 compounds were docked.The docking scores and the binding modes of ligand-protein complexes were analyzed.The docking results of 4a and 12 with four targets?PI3K?/?/?/??were better than ZSTK474.The docking scores of the other three compounds 4b,9a and 9b were equal to those of the control.2.Based on the result of the first part,5 compounds were synthesized.3.By investigating the effects of different concentrations of each compound on the proliferation of PC3 cells,it was found that 9a and 9b could significantly inhibit the proliferation of PC3 cells.4.Through virtual screening,docking,ADMET prediction and molecular dynamics simulation of Zinc database,ZINC28564067 was selected as PI3K?/?inhibitor with good docking result,low toxicity and good pharmacokinetic characteristics.5.The Ligand Expo database was screened by means of virtual screening,docking,ADMET prediction and molecular dynamics simulation.Finally,comp#L-1 was obtained as a potential PI3K?/?dual inhibitor.6.The structure of PI3K?inhibitor Idelalisib was modified using the combination principle,isosterism and scaffold hopping,and the modified compounds were docked.Comp#1 was obtained as a potential PI3K?inhibitor by docking,ADMET prediction and molecular dynamics simulation.Conclusion:Several groups of compounds with potential PI3K inhibitory activity were designed by computer-aided drug design methods,such as molecular docking,virtual screening,and scaffold hopping.A group of compounds were synthesized and their structures were confirmed by ¹H-NMR,¹³C-NMR and Mass spectrum.MTT assay showed that compounds 9a and 9b could inhibit the proliferation of PC3 cells,which laid a foundation for the development of anticancer drugs.