Lan Junjie, Wang Ning, Huang Lan, Liu Yazhou, Ma Xiaopan, Lou Huayong, Chen Chao, Feng Yibin, Pan Weidong
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, China; College of Pharmacy Guizhou University, Huaxi Avenue South, Guiyang 550025, China.
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam 999077, Hong Kong.
Eur J Med Chem. 2017 Feb 15;127:554-566. doi: 10.1016/j.ejmech.2017.01.008. Epub 2017 Jan 7.
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 IC = 1.06 μM (15.8 folds than that of tetrandrine, and 30.3 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.
粉防己碱是一种从药用植物粉防己中分离得到的具有双苄基四氢异喹啉骨架的先导抗肿瘤化合物。为了获得活性抗肿瘤药物并评估其构效关系，本研究设计并合成了一系列新型粉防己碱衍生物。还评估了它们对人肝癌细胞系（HMCC97L和PLC/PRF/5）的抗肿瘤活性。生物测定结果表明，这些衍生物对这两种细胞系表现出中度至强抑制作用。其中，化合物31表现出显著的细胞毒性，IC50 = 1.06 μM（是粉防己碱的15.8倍，索拉非尼的30.3倍）。对其作用机制的进一步研究表明，化合物31的体外抗肿瘤活性主要归因于诱导肝癌细胞凋亡。化合物31能够引发内质网应激相关的凋亡性细胞死亡，可能涉及JNK以及半胱天冬酶途径的激活。我们的结果表明，化合物31，一种新型的14位取代酰胺粉防己碱衍生物，可能是未来开发新型抗肝癌药物的潜在候选物。
