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[Display omitted] • Compound 2h is the most potent against A549 cells with the IC 50 value of 0.27 µM; • Compound 2h inhibits A549 proliferation and arrest A549 cells at G2/M cycle; • Compound 2h can influence A549 cell migration and invasion and induce cells apoptosis; • Compound 2h can inhibit the activation of PI3K/Akt/mTOR signaling pathway in vivo ; Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S. , which is a bis-benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthesized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC 50 value of 0.26 μM, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC 50 value of 27.05 μM. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel geniposide derivatives were designed and synthesized for discovering efficient XOD inhibitor. • Compound 2e displayed the most XOD inhibitory effect in vitro and in vivo. • Compound 2e can also repair kidney damage by inhibiting the expression of TNF-α and IL-1β signaling pathways. • Kinetics analysis revealed that compound 2e is a reversible mixed competitive inhibitor. • Molecular docking study indicated iridoid and glycosyl moiety of compound 2e were critical for binding to the XOD active site. Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC 50 value of 6.67 ± 0.46 µM. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-κB and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage. [ABSTRACT FROM AUTHOR]