| Summary: | Aiming at seeking an effective anti-hepatocarcinoma drug with low toxicity, a total of 24 amino acid derivatives (20 new along with 4 known derivatives) of two active ocotillol-type sapogenins (pyxinol and ocotillol) were synthesized. Both in vitro and in vivo anti-hepatocarcinoma effects of derivatives were evaluated. At first, the HepG2 human cancer cell was employed to evaluate the anti-cancer activity. Most of the derivatives showed obvious enhanced activity compared with pyxinol or ocotillol. Among them, compound <b>2e</b> displayed the most excellent activity with an IC<sub>50</sub> value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound <b>2e</b>. It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound <b>2e</b> or compound <b>2e</b> combined with cyclophosphamide (CTX) (<i>p</i> < 0.05, <i>p</i> < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound <b>2e</b> caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound <b>2e</b> was explored by serum and liver metabolomics based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. A total of 21 potential metabolites involved in 8 pathways were identified. These results suggest that compound <b>2e</b> is a promising agent for anti-hepato-carcinoma, and that it also could be used in combination with CTX to increase efficiency and to reduce toxicity.
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