Design and Synthesis of Novel 7-Ethyl-10-Fluoro-20-O-(Cinnamic Acid Ester)-Camptothecin Derivatives as Potential High Selectivity and Low Toxicity Topoisomerase I inhibitors for Hepatocellular Carcinoma

喜树碱 拓扑替康 细胞毒性 细胞培养 IC50型 细胞凋亡 G2水电站 化学 细胞毒性T细胞 毒性 拓扑异构酶 细胞生长 药理学 癌症研究 生物化学 体外 生物 有机化学 化疗 遗传学
作者
Yin-Peng Bai,Cheng-Jie Yang,Nan Deng,Mi Zhang,Zhijun Zhang,Lei Li,Yong Zhou,Xiongfei Luo,Chuanrui Xu,Baoqi Zhang,Yue Ma,Ying-Qian Liu
出处
期刊:Biochemical Pharmacology [Elsevier]
卷期号:200: 115049-115049
标识
DOI:10.1016/j.bcp.2022.115049
摘要

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.
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