Synthesis and Biological Evaluation of the Matrine Derivatives as a Novel Family of Potential Anticancer Agents.

BACKGROUND: FufangKushen injection' was a Chinese Traditional anticancer drug, which has been widely used to treat cancer in combination with other anticancer drugs. OBJECTIVE: Our goal is to synthesize a series of novel 13-dithiocarbamates matrine derivatives using matrine (1) as the lead compound, and evaluate the biological activities of the obtained compounds. METHODS: The in vitro cytotoxicity of the target compounds against three human cancer cell lines (Hep3B, LM3 and BeL-7404) was evaluated. To investigate the mechanism of biological activity, cell cycle analysis was performed. RESULTS: The results revealed that compounds 6o and 6v displayed the most significant anticancer activity against three cancer cell lines with IC50 values in the range of 3.42-8.05 µM, which showed better activity than the parent compound (Matrine). SAR analysis indicated that the introduction of a substituted amino dithiocarbamate might significantly enhance the antiproliferative activity. CONCLUSION: During the newly synthesized compounds, matrine analog 6v exhibited a potent effect against three human tumor cell lines. The mode of action of 6v was to inhibit the G0/G1 phase arrest. Therefore, compound 6v has been selected as a novel-scaffold lead to further structural optimizations or as a chemical probe for exploring anticancer pathways of this kind of compounds.

A novel matrine derivative WM622 inhibits hepatocellular carcinoma by inhibiting PI3K/AKT signaling pathways.

Hepatocellular carcinoma (HCC) is among the most common lethal cancers of the digestive system with poor prognosis rates and ineffective therapeutic options. Matrine, a traditional Chinese medicine found in the roots of sophora species, has been used in the clinical treatment of liver fibrosis, chronic hepatitis B and other diseases. We have synthesized a matrine derivatives named WM622 (C26H35ON3S2) with a significant inhibitory effect on transplanted tumors in vivo. The half inhibitory concentration (IC50) of WM622 is 34 µM, which is much lower than matrine. WM622 inhibited the proliferation and promoted apoptosis of hepatocellular carcinoma cells significantly, and the cell cycle was blocked in G0/G1 phase. The protein phosphorylation levels of EGFR, AKT, PI3K and GSK3ß (p-EGFR, p-AKT, p-PI3K, and p-GSK3ß) were also decreased by WM622 treatment dose dependently. In tumor-bearing mice, WM622 could reduce the tumor volumes. In conclusion, the study demonstrated that WM622 could inhibit the proliferation of the hepatocellular carcinoma both in vivo and in vitro by inducing apoptosis, blocking cell cycle in G0/G1 phase and inhibiting the PI3K/AKT signal pathways.