Design,Synthesis And Biological Evaluation Of Quinoline Derivatives Targeting Orphan Receptor Nur77

Nuclear receptor superfamily is a transcription factor widely distributed in eukaryotic and is also one of the significant targets for anti-tumor drug design Orphan nuclear receptor Nur77 is related to the growth,proliferation,differentiation and apoptosis of malignant tumors.Nur77 is one of the significant targets for anti-tumor drug design,and many small-molecule compounds have been found to affect cancer resistance by affecting expression changes of Nur77.In this paper,seven series of substituted quinoline derivatives,172 in total,have been designed and synthesized,and their structures were characterized.All these compounds have never been reported.Cytotoxicity experiments have been completed.Most of the compounds show good antitumor activity except series D.In HepG2,QGY-7703,SMMC-7721,L02,the IC50 of A3 is 4.61 ±0.19,6.38±0.20,14.02±1.05,16.94±1.03 μM seperately.Thus,we select A3 as our lead compound for further research.The IC50 of B11 in HepG2 is 0.21 ±0.04 μM.The IC50 of C22 is 0.02±0.01、1.32±0.40.0.02±0.01.4.53±1.45μM inQGY-7703,HepG2,SMMC-7721,LO2 separately.The inhibitory activity of C22 against tumor cells is significantly higher than normal cells.A3 could induce the overexpression of Nur77 in HepG2,QGY-7703,SMMC-7721 cells,which leads to various biological changes such as growth inhibition,endoplasmic reticulum stress and apoptosis with Immunohistochemistry and Western Blot results confirmed.Also 20.0 mg/kg/2day of A3 injection did not influence the body weights of the nude mice in the animal experiment,which indicates A3 has low toxicity to the nude mice.Protein methyltransferases can regulate the post-translational methylation modification of proteins.The dysregulation of protein methylation is related to the occurrence and development of various tumors.Therefore,protein methyltransferases are also potential targets for the design of anti-tumor drugs.We found some compounds binding to PRMT6 through high-throughput virtual screening.C32 can specifically act on PRMT6,inhibiting the methylation of its substrate,structural optimization is in progress.In summary,we design and synthesis 7 series of new compounds,172 in total in this paper.We finished the preliminary evaluation of biological activity and discussion of the structure-activity relationship.We got B11,A3,C22 and C32 for further biological activity studies.