European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2018-03-05 , DOI: 10.1016/j.ejmech.2018.03.010
Ning Zhang 1 , Zhimei Yu 1 , Xiaohong Yang 1 , Ping Hu 1 , Yun He 1
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Artemisinin is a potential anticancer agent with an interesting trioxane sesquiterpene structure. In order to improve the biological activity and metabolic stability of artemisinin, a series of novel ring-contracted artemisinin dimers were synthesized. These dimers were evaluated by MTT assay against six cancer cell lines. Most of the dimmers exhibited improved antiproliferative activities over artemisinin. Especially, compound 8b showed the most pronounced anti-cancer activity for PC12 cancer cells with an IC50 value of 1.56 μM. Thus, PC12 cancer cells were used to further investigate the mechanism of antiproliferation for this series of compounds. Compound 8b arrested cell cycle at G1 phase and induced cell apoptosis via up-regulation of Bad, Bax, caspase-3 and caspase-9 protein expressions while inhibiting the expression of Bcl-xL. The present studies are the first to synthesize the ring-contracted artemisinin as dimers and show that these dimers have potent anti-tumor activities against several cancer cell lines.
中文翻译:
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具有强抗癌活性的新型环收缩青蒿素二聚体的合成
青蒿素是一种潜在的抗癌剂,具有有趣的三恶烷倍半萜烯结构。为了提高青蒿素的生物活性和代谢稳定性,合成了一系列新型的环缩青蒿素二聚体。这些二聚体通过 MTT 测定针对六种癌细胞系进行评估。大多数调光剂表现出优于青蒿素的抗增殖活性。特别是化合物8b对PC12癌细胞显示出最显着的抗癌活性,IC 50值为1.56 μM。因此,PC12 癌细胞被用于进一步研究这一系列化合物的抗增殖机制。化合物8b通过上调 Bad、Bax、caspase-3 和 caspase-9 蛋白表达同时抑制 Bcl-xL 表达,将细胞周期阻滞在 G1 期并诱导细胞凋亡。本研究首次将环缩青蒿素合成为二聚体,并表明这些二聚体对几种癌细胞系具有有效的抗肿瘤活性。