Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma.
Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma.
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DOI：
10.1016/j.ejmech.2022.114166
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发表时间：
2022-02
影响因子：
6.7
通讯作者：
Yang Hai;Jiaqing Geng;Peng Li;W. Ma;Cui-Fang Wang;Mei-Yan Wei;Xue-Mei Hou;Guangying Chen;
中科院分区：
文献类型：
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作者：
Yang Hai;Jiaqing Geng;Peng Li;W. Ma;Cui-Fang Wang;Mei-Yan Wei;Xue-Mei Hou;Guangying Chen;
肝细胞癌是最常见的原发性肝脏恶性肿瘤之一。本文中，制备了天然产物（+）-sclerosis in（1）的一系列半合成衍生物（2-30），并评价了其对六种癌细胞系的细胞毒活性。其中化合物3和化合物5对人肝癌Bel-7402细胞的抑制作用最强，其IC_（50）值分别为1.45和1.15μM。分子机制研究表明，5以半胱天冬酶依赖的方式破坏线粒体膜电位，诱导细胞凋亡。此外，5-羟基喹啉还通过泛素-蛋白酶体系统影响AKT和ERK信号通路，诱导AKT和ERK蛋白降解。在裸鼠移植瘤模型中，5号具有明显的体内抗肿瘤作用，肿瘤体积减小52.5%。通过急性毒性试验、亚慢性毒性试验、小鼠脏器石蜡切片和血常规检查，证实了其安全性。因此，5-羟色胺可作为一种潜在的肝癌治疗药物。
Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives (2–30) of the natural product (+)-sclerotiorin (1) was prepared and evaluated the cytotoxic activities against six cancer cell lines. Among them,3and5were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC50values of 1.45 and 1.15μM, respectively. Molecular mechanism study showed that5disrupted the mitochondrial membrane potential and induced apoptosis in a caspase-dependent manner. In addition,5affected AKT and ERK signaling pathways and induced AKT and ERK proteins degradation through ubiquitin-proteasome system. Furthermore,5displayed significantin vivoanticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together,5can be developed as a potential therapeutic agent for hepatocellular carcinoma.