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Using the Cancer Dependency Map to Identify the Mechanism of Action of a Cytotoxic Alkenyl Derivative from the Fruit of Choerospondias axillaris.
Journal of Natural Products ( IF 5.1 ) Pub Date : 2020-02-27 , DOI: 10.1021/acs.jnatprod.9b00896
Yun-Seo Kil 1 , April L Risinger , Cora L Petersen , Huiyun Liang , Tanja Grkovic 2 , Barry R O'Keefe 3, 4 , Susan L Mooberry , Robert H Cichewicz 1
Affiliation  

An extract prepared from the fruit of Choerospondias axillaris exhibited differential cytotoxic effects when tested in a panel of pediatric cancer cell lines [Ewing sarcoma (A-673), rhabdomyosarcoma (SJCRH30), medulloblastoma (D283), and hepatoblastoma (Hep293TT)]. Bioassay-guided fractionation led to the purification of five new hydroquinone-based metabolites, choerosponols A-E (1-5), bearing unsaturated hydrocarbon chains. The structures of the natural products were determined using a combination of 1D and 2D NMR, HRESIMS, ECD spectroscopy, and Mosher ester analyses. The purified compounds were evaluated for their antiproliferative and cytotoxic activities, revealing that 1, which contains a benzofuran moiety, exhibited over 50-fold selective antiproliferative activity against Ewing sarcoma and medulloblastoma cells with growth inhibitory (GI50) values of 0.19 and 0.07 μM, respectively. The effects of 1 were evaluated in a larger panel of cancer cell lines, and these data were used in turn to interrogate the Project Achilles cancer dependency database, leading to the identification of the MCT1 transporter as a functional target of 1. These data highlight the utility of publicly available cancer dependency databases such as Project Achilles to facilitate the identification of the mechanisms of action of compounds with selective activities among cancer cell lines, which can be a major challenge in natural products drug discovery.

中文翻译:

使用癌症依赖性图确定来自 Choerospondias axillaris 果实的细胞毒性烯基衍生物的作用机制。

当在一组儿科癌细胞系 [尤文肉瘤 (A-673)、横纹肌肉瘤 (SJCRH30)、髓母细胞瘤 (D283) 和肝母细胞瘤 (Hep293TT)] 中进行测试时,从腋窝的果实中提取的提取物表现出不同的细胞毒性作用。生物测定引导的分馏导致了五种新的基于氢醌的代谢物的纯化,choerosponols AE (1-5),带有不饱和烃链。天然产物的结构是使用 1D 和 2D NMR、HRESIMS、ECD 光谱和 Mosher 酯分析的组合确定的。对纯化的化合物的抗增殖和细胞毒活性进行了评估,结果表明 1 含有苯并呋喃部分,对尤文肉瘤和髓母细胞瘤细胞表现出超过 50 倍的选择性抗增殖活性,其生长抑制 (GI50) 值分别为 0.19 和 0.07 μM。在更大范围的癌细胞系中评估了 1 的影响,这些数据依次用于询问跟腱项目癌症依赖性数据库,从而将 MCT1 转运蛋白识别为 1 的功能目标。这些数据突出了利用公开可用的癌症依赖性数据库(例如 Project Achilles)来促进识别癌细胞系中具有选择性活性的化合物的作用机制,这可能是天然产物药物发现的主要挑战。
更新日期:2020-02-27
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