Design and synthesis of novel tetrandrine derivatives as potential antitumor agents against human hepatocellular carcinoma
Design and synthesis of novel tetrandrine derivatives as potential antitumor agents against human hepatocellular carcinoma
复制标题
新型粉防己碱衍生物的设计与合成作为潜在的抗人肝细胞癌抗肿瘤药物
DOI：
10.1016/j.ejmech.2017.01.008
复制
发表时间：
2017-02-15
影响因子：
6.7
通讯作者：
Pan, Weidong
中科院分区：
文献类型：
--
作者：
Lan, Junjie;Wang, Ning;Pan, Weidong
粉防己碱，一种从药用植物粉防己中分离出来的具有双苄基四氢异喹啉骨架的主要抗肿瘤化合物。为了获得活性抗肿瘤药物并评价其构效关系，本研究设计合成了一系列新型粉防己碱衍生物。还评估了它们对人肝细胞癌细胞系（HMCC97L 和 PLC/PRF/5）的抗肿瘤活性。生物测定结果表明，衍生物对两种细胞系表现出中度至强的抑制作用。其中，化合物31表现出显着的细胞毒性，IC50=1.06μM（是粉防己碱的15.8倍，是索拉非尼的303倍）。进一步的机制研究表明，化合物31的体外抗肿瘤活性主要是由于诱导HCC细胞凋亡。化合物 31 能够启动内质网应激相关的细胞凋亡，并且可能涉及 JNK 和 caspase 途径的激活。我们的结果表明，化合物 31（一种新的 14 位取代酰胺粉防己碱衍生物）可能是未来开发新型抗 HCC 药物的潜在候选者。 (c) 2017 年 Elsevier Masson SAS。版权所有。
Tetrandrine, a lead anti-tumor compound with a bis-benzyltetrahydroisoquinoline skeleton isolated from medicinal plant Stephania tetrandra. In order to obtain active anti-tumor agents and evaluate their structure-activity relationships, a series of novel tetrandrine derivatives were designed and synthesized in this study. Their anti-tumor activities against human hepatocellular carcinoma cell lines (HMCC97L and PLC/PRF/5) were also evaluated. The bioassay results showed that the derivatives exhibited moderate to strong inhibition against the two cell lines. Among them, compound 31 showed prominent cytotoxicity with IC50 = 1.06 mu M (15.8 folds than that of tetrandrine, and 303 folds than that of Sorafenib). Further studies on the mechanisms demonstrated that the in vitro anti-tumor activity of compound 31 was predominantly due to the inducement of apoptosis of HCC cells. Compound 31 was capable of initiating endoplasmic reticulum stress-associated apoptotic cell death, and the activation of JNK as well as caspase pathways were probably involved. Our results suggest that compound 31, a new 14-position substituted amide tetrandrine derivative, might be a potential candidate for developing novel anti-HCC drugs in the coming future. (c) 2017 Elsevier Masson SAS. All rights reserved.