| Objective:Mogrol is the aglycone of mogroside V in Siraitia grosvenorii（Swingle）C.Jeffrey,which is a special medicinal and edible plant in Guangxi.Previous research has found that mogrol is the component entering into blood of mogrosides metabolism in vivo,shows remarkable inhibitory activity on A549 cells,and can induce cell apoptosis and G0/G1 phase arrest.Non-small cell lung cancer（NSCLC）is the most common type of lung cancer,accounting for about 85%.The early diagnosis of NSCLC is difficult,and the overall treatment effect is poor in the middle and late stages.Although the targeted therapy and immunotherapy methods have made some progress,the relative survival rate is still low.Therefore,it is of great scientific significance and clinical value to find new therapeutic targets and drugs.In order to improve the anti-NSCLC activity of mogrol,we designed and synthesized various types of mogrol derivatives,evaluated the inhibitory activity by Cell Counting Kit-8（CCK8）assay in vitro,investigated the structure-activity relationship,and preliminarily explored the anti-lung cancer mechanism of active derivative.Methods:The C3,C11,C24 and A ring of mogrol were modified through natural product hybridization strategy.Various groups including quinoline motif,indole ring,1,2,3-triazole ring,aromatic ring and aliphatic ring were introduced.The structures of the synthesized derivatives were identified by 1H-NMR,13C-NMR and HR-ESI-MS.CCK8 method was used to investigate the inhibitory activities of derivatives against A549 and NCI-H460 cell lines.Cell apoptosis and cell cycle were detected by flow cytometry,and the phosphorylation of signal transduction factor and transcription activator 3（STAT3）was detected by Western blotting method.Molecular docking was used to study the binding mode between active derivative and STAT3 target.Results:Four series of 46derivatives were designed and synthesized based on mogrol.According to the result,most compounds showed higher inhibitory activity against A549 and NCI-H460 cells than mogrol.The C11 hydroxyl substitution was beneficial to the enhancement of the activity,especially the introduction of 1,2,3-triazole group;C3 hydroxyl substitution was more beneficial to improve the antiproliferative activity against NCI-H460 cells.The structural modification at C24 had positive effect on anti-tumor activity,but the effect is not obvious.A-ring modification could significantly enhance the inhibitory activity of NCI-H460,while the retention of C11 hydroxyl was more favorable.The IC50value of compound 4f connecting 1,2,3-triazole ring with ester bond was 4.47μM against A549 cells.The mechanism experiment showed that compound 4f induced A549 cell apoptosis and G0/G1 phase arrest,and downregulated the expression level of p-STAT3.Furthermore,molecular docking showed that compound 4f could closely integrated through hydrogen bond and hydrophobic interaction with the three pockets of the SH2 domain.Conclusion:Appropriate structural modification can significantly improve the anti-lung cancer activity of mogrol.Active derivatives exert anti-proliferation activity through the regulation of STAT3 pathway,and induce apoptosis and cycle arrest.This paper enriches the structural types of mogrol derivatives and lays a foundation for the discovery and development of anti-lung cancer lead compounds based on mogrol. |
