Graduate School of Informatics, Cancer Systems Biology Laboratory, METU, 06800, Ankara, Turkey.
Department of Chemistry, University of Durham, South Road, DH1 3LE, Durham, UK.
Eur J Med Chem. 2019 Mar 15;166:243-255. doi: 10.1016/j.ejmech.2019.01.056. Epub 2019 Jan 24.
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.
已经通过简短高效的方法合成了两类波罗米亚辛 A 类似物，这些类似物在生物碱的五环骨架或其外围取代模式上存在差异。这两类类似物使人们首次能够对关键的生物学特性进行比较研究，揭示出一种新的先导化合物，对分化良好（Huh7、Hep3B 和 HepG2）和分化较差（Mahlavu、FOCUS 和 SNU475）的肝癌细胞系具有极高的活性，其活性达到皮摩尔级。细胞死亡通过细胞色素 C 释放、PARP 蛋白切割和 SubG1 细胞周期停滞被鉴定为细胞凋亡。随后的测试通过活性氧（ROS）的原位形成和磷酸化蛋白水平的改变来确定与凋亡相关的氧化应激。化合物 19 降低了 Akt 蛋白磷酸化，这在肝癌肿瘤发生中起着至关重要的作用。鉴于其简单的可合成性和有趣的生物学特性，这种新的先导化合物可能会解决肝癌治疗中的未满足的挑战。
