Abstract
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 2e displayed the most excellent activity with an IC50 value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound 2e. It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound 2e or compound 2e combined with cyclophosphamide (CTX) (p < 0.05, p < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound 2e caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound 2e 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 2e 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.
Highlights
IntroductionThe fourth major lethal malignancy worldwide, is generally divided into HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) and MHC (mixed hepato- cellular and cholangiocellular carcinoma) based on the pathological classification [1]
Liver cancer, the fourth major lethal malignancy worldwide, is generally divided into HCC, ICC and MHC based on the pathological classification [1]
It was reported that pyxinol exhibited multiple pharmacological activities such as anti-cancer [20,21,22], anti-multidrug resistance [11] and anti-inflammatory [23], etc
Summary
The fourth major lethal malignancy worldwide, is generally divided into HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) and MHC (mixed hepato- cellular and cholangiocellular carcinoma) based on the pathological classification [1]. Numerous scientific researchers devoted themselves to the modification or transformation of lead compounds with the purpose of obtaining derivative products with good properties [5,6,7,8]. Natural products and their structurally modified derivatives have been widely used as anti-tumor drugs due to the low toxicity and the ability of reversing multidrug resistance [9,10,11,12]. From all the above facts, we anticipated that amino acid conjugated ocotillol-type sapogenin might result in new leads possessing good pharmacological activities
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