A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (
hepatocellular carcinoma), SW480 (
colorectal cancer), A2780 (
ovarian cancer), and Hucct1 (
intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the
camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC50 values of 0.03, 0.09, 0.22, and 0.32 μM, respectively. Further investigation demonstrated that compound XJS-11 exhibited more effective growth inhibition against a variety of human
hepatoma cells (Sk-hep-1, Hep3B and Huh7) and lower cytotoxicity against immortalized normal human liver cell line L02 than the positive control
topotecan. Especially, XJS-11 showed higher selective toxicity in two kinds of human
hepatoma cells and immortalized normal human liver cell line (IC50(L-02)/IC50(HepG2) = 113.20; IC50(L-02)/IC50(Hep3B) = 85.60) than
topotecan (IC50(L-02)/IC50(HepG2) = 9.45; IC50(L-02)/IC50(Hep3B) = 8.52). Mechanistically, XJS-11 induced cell cycle arrest and cell apoptosis in HepG2 and Hep3B cells by inhibiting Top I activity in a manner similar to that of
topotecan. Meanwhile, XJS-11 could attenuate the
tumor growth in both xenograft and primary HCC mouse models. In addition, the acute toxicity assay showed that XJS-11 did not cause lethality or significant
body weight loss with a single intraperitoneal dose at 100 mg/kg or with an intraperitoneal dose at 25 mg/kg for 7 days. Moreover, unlike
topotecan, XJS-11 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the C57BL/6 mice. Taken together, XJS-11 merits further development as a new generation of the
camptothecin-derived
drug candidate.