Monoterpenoid indole alkaloid dimers from Kopsia arborea inhibit cyclin-dependent kinase 5 and tau phosphorylation

Chen Chen; Jian-Wen Liu; Ling-Li Guo; Feng Xiong; Xiao-Qian Ran; Ya-Rong Guo; Yong-Gang Yao; Xiao-Jiang Hao; Rong-Can Luo; Yu Zhang

doi:10.1016/j.phytochem.2022.113392

Monoterpenoid indole alkaloid dimers from Kopsia arborea inhibit cyclin-dependent kinase 5 and tau phosphorylation

Phytochemistry. 2022 Nov:203:113392. doi: 10.1016/j.phytochem.2022.113392. Epub 2022 Aug 27.

Authors

Chen Chen¹, Jian-Wen Liu¹, Ling-Li Guo¹, Feng Xiong¹, Xiao-Qian Ran², Ya-Rong Guo³, Yong-Gang Yao², Xiao-Jiang Hao⁴, Rong-Can Luo⁵, Yu Zhang⁶

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, And KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650201, Yunnan, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, And KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, Yunnan, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, Anhui, China.
⁴ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China; Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China. Electronic address: haoxj@mail.kib.ac.cn.
⁵ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, And KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650201, Yunnan, China. Electronic address: luorongcan@mail.kiz.ac.cn.
⁶ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China. Electronic address: zhangyu@mail.kib.ac.cn.

PMID: 36030903
DOI: 10.1016/j.phytochem.2022.113392

Abstract

Three undescribed monoterpenoid indole alkaloid dimers (kopoffines A-C, which are connected via a methylene unit) and with nine known alkaloids were isolated and identified from the fruits of Kopsia arborea Blume. Their structures, including their absolute configurations, were established by HRESIMS, NMR, single-crystal X-ray diffraction, and ECD analyses. Kopoffines A-C showed significant inhibition against cyclin-dependent kinase 5 (IC₅₀: 0.34-2.18 μM). Western blotting analyses showed that kopoffines A-C significantly decreased the protein levels of CDK5 and phospho-CDK5 (Tyr15) (pCDK5) at concentrations of 2.5 and 10 μM. The levels of phospho-Tau (Thr217) (pTau217, a new biomarker of AD), and phospho-Tau (Ser396) (pTau396), which play major roles in the formation of neurofibrillary tangles , were decreased by the kopoffines A-C treatment. Molecular docking studies indicated that kopoffines A-C could form stable interactions with CDK5.

Keywords: Apocynaceae; Cyclin-dependent kinase 5; Kopoffines A-C; Kopsia arborea Blume; Monoterpenoid indole alkaloids; Tau phosphorylation.

MeSH terms

Apocynaceae* / chemistry
Cyclin-Dependent Kinase 5
Indole Alkaloids / chemistry
Molecular Docking Simulation
Molecular Structure
Monoterpenes
Phosphorylation
Secologanin Tryptamine Alkaloids* / pharmacology

Substances

Indole Alkaloids
Monoterpenes
Secologanin Tryptamine Alkaloids
Cyclin-Dependent Kinase 5