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Brunonianines D-F是来自Delphinium brunonianum的三种新的C19-二萜生物碱,在体外和体内对卵巢癌具有治疗作用。

Brunonianines D-F, three new C19-diterpenoid alkaloids from the Delphinium brunonianum, with therapeutic effect on ovarian cancer in vitro and in vivo.

发表日期:2024 May 19
作者: Qing Li, Min-Min Gu, Hong-Wei Wu, Chen-Sen Xu, Hao-Lin Yu, Yu Zhang, Yun-Yun Su, Hong-Ping Han, Zhi-Xin Liao
来源: BIOORGANIC CHEMISTRY

摘要:

目前卵巢癌的标准治疗方法包括手术缩小肿瘤大小,然后使用化疗药物治疗,但化疗药物具有很大的副作用。因此,寻找副作用较少的天然产物新药是一种策略。布鲁诺翠雀 (D. brunonianum) 是一种传统藏药,主要产自中国西藏南部,但这种植物的化学成分仍然难以捉摸。通过 HPLC 和各种柱色谱技术分析和纯化 D. brunonianum 二氯甲烷部分中的主要代谢物。从 D. brunonianum 中分离得到 9 种二萜生物碱 (1-9) 和 1 种酰胺生物碱 (10),其中包括 3 种新型 C19 型二萜生物碱 (Brunonianines D-F) (1-3)。通过 1D/2D NMR、HR-ESI-MS 和单晶 X 射线衍射分析阐明了它们的结构。所有化合物均在四种肿瘤细胞系中进行毒性评估。大多数化合物对 Skov-3 细胞系表现出有效的抑制作用,IC50 值范围为 2.57 至 8.05 μM。通过western blotting实验进一步分析化合物1的Bax/Bcl-2/Caspase-3信号通路分子的表达水平。通过分子对接预测Brunonianine D与靶蛋白的结合模式。还通过监测 Skov-3 肿瘤的大小进行实时体内实验和评估。此外,肿瘤H
The current standard treatment for ovarian cancer consists of surgery to reduce the size of the tumor, followed by treatment with chemotherapeutic drugs, which have major side effects. Therefore, finding a new natural product drug with fewer side effects is a strategy. Delphinium brunonianum (D. brunonianum) is a traditional Tibetan medicine, mainly from southern Tibet, China, whereas the chemical constituents in this plant remain elusive. The major metabolites in the dichloromethane fraction of D. brunonianum were analyzed and purified by HPLC and various column chromatography techniques. Nine diterpenoid alkaloids (1-9) and one amide alkaloid (10) were isolated from D. brunonianum, including three novel C19-type diterpenoid alkaloids (Brunonianines D-F) (1-3). Their structures were elucidated by 1D/2D NMR, HR-ESI-MS and single-crystal X-ray diffraction analyses. All compounds were evaluated for toxicity in four tumor cell lines. Most of the compounds exhibited potent inhibitory effects on Skov-3 cell lines, with IC50 values ranging from 2.57 to 8.05 μM. The western blotting experiment was used to further analyze the expression levels of molecules in the Bax/Bcl-2/Caspase-3 signaling pathway for compound 1. Molecular docking was performed to predict the binding modes of Brunonianine D with target proteins. In vivo experiments were also performed and evaluated in real time by monitoring the size of the Skov-3 tumor. Additionally, tumor H&E staining and the TUNEL assay used to evaluate anti-tumor effects.Copyright © 2024. Published by Elsevier Inc.