Design,Synthesis And Activity Study Of Isoindoline PDE4 Inhibitors

Non-small-cell lung cancer（NSCLC）is the most common pathological type of lung cancer,which seriously threatens human life and health.Existing drugs for NSCLC are poor in potency and have serious side effects.Therefore,the development of highly effective and low toxic drugs for the treatment of NSCLC has become a hotspot in medical research.In this study,high throughput screening technology was used to screen Top Science commercial small molecule library.Four compounds with good apoptosis effect on TP53-deleted NSCLC line Calu-1（squamous cell carcinoma）were obtained.Among them,compound 101 showed better apoptosis effect on Calu-1 cell line than other three compounds(IC₅₀=3.55μM),and more importantly,it had no significant effect on normal cells.On this basis,compound 101 was selected as the lead compound,and 11 novel isoindoline analogues were designed and synthesized.The compounds were confirmed by ¹H NMR,¹³C NMR and HR-MS,and the relationship between structure and biological activity was further analysed.In the aspect of bioactivity test,we have completed 11 isoindolin analogues to inhibit the activity of NSCLC.The results showed that the apoptosis activity of isoindolin derivatives and tetrahydroisoquinoline derivatives increased by two and four times,respectively.In addition,although isoindolinedione derivatives and benzoxazine derivatives had no obvious killing effect on NSCLC,they also provided design ideas for isoindolin analogues to some extent,and furthermore,explored the structure activity relationship of therapeutic drugs for NSCLC,and provides a reference for the research and development of new drugs for the treatment of NSCLC.