ent-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition As Detected in Situ by a Fluorescence Probe
ent-Kaurane Diterpenoids from Chinese Liverworts and Their Antitumor Activities through Michael Addition As Detected in Situ by a Fluorescence Probe
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荧光探针原位检测地草中的对映贝壳杉烷二萜及其迈克尔加成的抗肿瘤活性
DOI：
10.1021/acs.jmedchem.5b00208
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发表时间：
2015-05-14
影响因子：
7.3
通讯作者：
Lou, Hongxiang
中科院分区：
文献类型：
--
作者：
Lin, Zhaomin;Guo, Yanxia;Lou, Hongxiang
普遍认为，对映贝壳杉烷型二萜类化合物的细胞毒性的起源是由于活性氧（ROS）的形成，并且α，β-不饱和羰基是关键部分。本文报道了从两种苔类植物中分离得到的32个新化合物和12个已知化合物。这些化合物和三个半合成的衍生物对人类癌细胞系进行了筛选。结果表明，它们的抗肿瘤活性是通过Michael修饰蛋白质巯基形成活性氧和非选择性地消耗谷胱甘肽引起的。我们还发现，N-乙酰半胱氨酸逆转这些二萜类化合物的细胞毒性形成迈克尔加合物，而不是通过公认的活性氧清除途径，如以前报道的。原位细胞内巯基检测帮助我们可视化的二萜类化合物的细胞内分布，并确定其细胞毒性的效力。碱性类似物被认为是更有选择性的，因为改变了亚细胞分布。
It is generally accepted that the origin of the cytotoxicity of ent-kaurane diterpenoids is due to the formation of reactive oxygen species (ROS) and that the alpha,beta-unsaturated carbonyl is a pivotal moiety. Herein we demonstrate the isolation of 32 new and 12 known ent-kaurane diterpenoids from two Chinese liverworts. These compounds and three semisynthesized derivatives were screened against human cancer cell lines. The results revealed that their anticancer activities are caused by ROS formation through Michael modification of the protein thiols and depletion of glutathione unselectively. We also found that N-acetylcysteine reverses the cytotoxicity of these diterpenoids by forming Michael adducts, not through a well-recognized ROS scavenging pathway as previously reported. In situ intracellular thiol detection helped us visualize the intracellular distribution of the diterpenoids and determine the potency of their cytotoxicity. An alkaline analogue was found to be more selective because of the altered subcellular distribution.