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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis of new derivatives of boehmeriasin A and their biological evaluation in liver cancer
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Synthesis of new derivatives of boehmeriasin A and their biological evaluation in liver cancer

机译：致沸虫A的新衍生物及其在肝癌中的生物学评价

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摘要

Two series of boehmeriasin A analogs have been synthesized in short and high yielding processes providing derivatives differing either in the alkaloid's pentacyclic scaffold or its peripheral substitution pattern. These series have enabled, for the first time, comparative studies into key biological properties revealing a new lead compound with exceptionally high activity against liver cancer cell lines in the picomolar range for both well (Huh7, Hep3B and HepG2) and poorly (Mahlavu, FOCUS and SNU475) differentiated cells. The cell death was characterized as apoptosis by cytochrome-C release, PARP protein cleavage and SubG1 cell cycle arrest. Subsequent testing associated apoptosis via oxidative stress with in situ formation of reactive oxygen species (ROS) and altered phospho-protein levels. Compound 19 decreased Akt protein phosphorylation which is crucially involved in liver cancer tumorigenesis. Given its simple synthetic accessibility and intriguing biological properties this new lead compound could address unmet challenges within liver cancer therapy. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：在短期和高收益过程中已经合成了两系列BoehmeriaIn A类似物，提供了在生物碱的五环支架或其外围替代模式中不同的衍生物。这些系列首次启用了比较研究，该研究是关键的生物学性质，揭示了井（Huh7，Hep3b和Hepg2）和糟糕（Mahlavu，Focus的肝脏癌细胞系中肝癌细胞系的新铅化合物和snu475）差异化细胞。细胞死亡表征为细胞色素-C释放的细胞凋亡，PARP蛋白质切割和SubG1细胞周期停滞。随后通过具有反应性氧物质（ROS）的原位形成和改变磷蛋白水平的氧化应激的相关凋亡。化合物19下降的Akt蛋白磷酸化，其决定性地参与在肝癌肿瘤发生。鉴于其简单的合成可互动性和有趣的生物学性质，这种新的铅化合物可以解决肝癌治疗中的未满足挑战。 （c）2019年Elsevier Masson SAS。版权所有。

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