Efficient Synthesis of Icetexane Diterpenes and Apoptosis Inducing Effect by Upregulating BiP-ATF4-CHOP Axis in Colorectal Cells
Efficient Synthesis of Icetexane Diterpenes and Apoptosis Inducing Effect by Upregulating BiP-ATF4-CHOP Axis in Colorectal Cells
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DOI：
10.1021/acs.jnatprod.1c00310
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发表时间：
2021-06-25
影响因子：
5.1
通讯作者：
Deng, Xu
中科院分区：
文献类型：
--
作者：
Cao, Wei;Liu, Tingting;Deng, Xu
本文提出了一种高效、稳健的合成12个十六烷二萜及其衍生物的方法，其特征在于PPh 3/DIAD介导的还原鼠尾草酸衍生物（2）的重排以区域选择性和可放大的方式得到（-）-barbatusol（3）。MTT测定导致鉴定出（+）-grandione（11）和（-）-去甲基salvicanol邻醌衍生物（9）作为针对HCT-116、科洛-205和Caco-2细胞的高细胞毒性剂。有趣的是，（+）-grandione（11）以剂量依赖的方式诱导HCT-116细胞凋亡，这可能归因于上调BiP-ATF 4-CHOP轴和促进BiP-ATF 4相互作用，从而导致内质网（ER）应激。这项工作不仅为获得icetexane二萜铺平了一条有效和可扩展的途径，而且为开发具有独特作用模式的抗结肠直肠药物提供了新的线索。
We herein present an efficient and robust synthetic strategy toward 12 icetexane diterpenes and their derivatives, which features a PPh3/DIAD-mediated rearrangement of the reduced carnosic acid derivative (2) to give (-)-barbatusol (3) in a regioselective and scalable way. MTT assay led to the identification of (+)-grandione (11) and (-)-demethylsalvicanol o-quinone derivative (9) as highly cytotoxic agents against HCT-116, COLO-205, and Caco-2 cells. Interestingly, (+)-grandione (11) induced the HCT-116 cell apoptosis in a dose-dependent manner, which might be attributed to the upregulation of the BiP-ATF4-CHOP axis and promotion of the BiP-ATF4 interactions, thereby leading to endoplasmic reticulum (ER) stress. This work not only paves an efficient and scalable pathway to access icetexane diterpenes but also provides new leads for the development of anticolorectal agents with a unique mode of action.