Design and synthesis of novel celastrol derivative and its antitumor activity in hepatoma cells and antiangiogenic activity in zebrafish
Design and synthesis of novel celastrol derivative and its antitumor activity in hepatoma cells and antiangiogenic activity in zebrafish
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DOI：
10.1002/jcp.28312
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Gong, Zhu-nan
中科院分区：
文献类型：
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作者：
Wang, Gang;Xiao, Qi;Gong, Zhu-nan
以雷公藤红素为原料，设计并合成了两个系列的雷公藤红素衍生物，分别在28位的羧酸上进行氨基酸修饰，在3位的羧酸上进行异丁酸酯修饰。所有化合物通过四种人癌细胞系（SCG 7901、HGC 27、HepG 2和Bel 7402）和一种正常细胞LO 2来评价其抗增殖活性。其中化合物8具有上级的生物活性和较低的毒性。进一步的基础实验表明，化合物8通过抑制信号转导子和转录激活子-3信号通路，诱导人肝癌细胞凋亡，使细胞阻滞于G2/M期，抑制细胞增殖和迁移。此外，建立了一种高准确度和重现性的高效液相色谱法测定斑马鱼对雷公藤红素和化合物8的吸收，结果表明，它们的浓度在4 h内以时间依赖性的方式迅速增加，并且化合物8的浓度高于雷公藤红素。此外，在12小时未检测到，化合物8在体内快速代谢。这些发现对于雷公藤红素等生物活性物质的结构修饰，提高其生物活性、毒性和吸收具有重要意义。
Two series of celastrol derivatives were designed and synthesized by modifying carboxylic acid at the 28th position with amino acid, and their intermediates with isobutyrate at the third position. All compounds were evaluated for their antiproliferation activity by four human cancer cell lines (SCG7901, HGC27, HepG2, and Bel7402) and one normal cell LO2. The most promising compound, compound 8, showed superior bioactivity and lower toxicity than others including celastrol. Further underlying tests illustrated that compound 8 induced apoptosis and cell arrest at G2/M and inhibited proliferation and mobility of human hepatoma cells by suppressing the signal transducer and activator of transcription-3 signaling pathway. Besides these, a highly accurate and reproducible high performance liquid chromatography protocol was established to determine celastrol and compound 8 absorption in zebrafish, and results demonstrated that their concentration increased rapidly within 4hr in a time-dependent manner and the concentration of compound 8 was higher than that of celastrol. In addition, without detection at 12hr, compound 8 was rapidly metabolized in vivo. These findings are very helpful for the structural modification of celastrol and other bioactive compounds to improve their bioactivity, toxicity, and absorption.