Abstract
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma.
Highlights
Published: 17 January 2022Hepatocellular carcinoma (HCC), one of the most lethal cancers, is highly metastatic and invasive
The low polarity and large doses limited the druglikeness of U12
(HepG2 cells were treated with different on viability of HepG2, Huh7, SMMC-7721 cells by methylthiazolyldiphenyltetrazolium bromide (MTT) assay. (HepG2 cells were treated with concentrations of U12a or U12 for 24 h, stained with MTT, and the optical density (OD) value was measured at a different concentrations of U12a or U12 for 24 h, stained with MTT, and the OD value was measured wavelength of 490 nm.) All data represent the mean ± SD of three independent experiments. ** p
Summary
Hepatocellular carcinoma (HCC), one of the most lethal cancers, is highly metastatic and invasive. HS-1183, a conjugate of UDCA with an L-phenylalanine benzyl ester, was reported to exert anti-tumor effects by inducing the apoptosis of human breast and prostate cancer cell lines through a p53-independent pathway, and preventing the death of human cervical carcinoma cells via nuclear translocation of NF-κB and activation of the JNK pathway, while it was to be cleaved by intestinal and hepatic enzymes [19,20,21]. Another effective way to improve the cytotoxic activity against cancer cells was to introduce nitrogen heterocycles, especially for the piperazine and cinnamylpiperazinyl group [22,23].
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