2. Academic Validation
  3. 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

  • J Nat Prod. 2021 Jul 23;84(7):2012-2019. doi: 10.1021/acs.jnatprod.1c00310.
Wei Cao 1,  Tingting Liu 1,  Shuting Yang 1,  Moude Liu 1,  Zhenghong Pan 2,  Yingjun Zhou 1 3,  Xu Deng 1 3
Affiliations

Affiliations

  • 1 Xiangya School of Pharmaceutical Science, Central South University, Changsha, 410013 Hunan, China.
  • 2 Guangxi Key laboratory of Functional Phytochemicals Research and Utilization, Guangxi Institute of Botany, Guangxi Zhuang Autonomous Region and Chinese Academy of Sciences, Guilin 541006, China.
  • 3 Hunan Key laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013 Hunan, China.
PMID: 34170142 DOI: 10.1021/acs.jnatprod.1c00310
Abstract

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.

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