Design, Synthesis And Antitumor Activity Of Benzo-pentacyclic PIM Inhibitor

Moloney murine leukemia viral proviral integration kinases（PIMs）regulate many tumor-forming pathways by phosphorylating target proteins,thereby activating or inactivating proteins involved in cell cycle progression,apoptosis,migration,or metabolism.Due to the role of PIM kinase in regulating the proliferation of tumor cells,its targets and inhibitors have attracted more and more attention.In this study,the existing PIM inhibitor compound 1 was used as the lead compound,and 30 benzodiacal heterocyclic compounds were designed through the principles of bioelectronic isoarrangement and local modification,combined with drug-assisted design software.The molecular docking results showed that the compounds had good interaction with proteins.The reverse synthesis of the compound was analyzed,and the suitable synthesis route was determined and the process was optimized considering the cheap and easy availability of raw materials,mild reaction conditions and simple operation.Finally,30 target compounds were synthesized by substitution,Suzuki reaction and deprotective group.The compounds were characterized by ¹HNMR,¹³CNMR and MS.With AZD1208 as the positive control,human colon cancer cell HCT-116 and human breast cancer cell MCF-7 as the test cell lines,the anti-tumor activity of the synthesized target compounds was evaluated by MTT assay.The results showed that most of the compounds inhibited HCT-116 and MCF-7 better,and the compounds inhibited HCT-116 better than MCF-7.The compounds with higher or closer inhibition than the positive control were selected for re-screening,and for HCT-116,the IC₅₀ values of compounds A2,A3,A4,B4,C5,C6,C8,C9,C10,D2,D3 and E3 were smaller than the positive control;for MCF-7,the IC₅₀ values of compounds A1,A2,A3,A4,B2,B4,C2 and C10 were smaller than the positive control.The structure-activity relationship of the target compounds was summarized.The results showed that the indole-ring as parent nucleus was more conducive to improving the activity of the target compounds than the thiazole ring,the p-fluorophenyl substitution on the indole-ring was more conducive to improving the activity than the phenyl substitution on the indole-ring,the electron-absorbing substitution activity of the urea fragment was higher than that of the electron donor,and the NH group on the indole-ring was the key active group.The results of this study lay a foundation for the follow-up study of PIM inhibitors.