Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity

doi:10.1007/s13659-025-00522-x

Natural Products and Bioprospecting ›› 2025, Vol. 15 ›› Issue (4): 38-38.DOI: 10.1007/s13659-025-00522-x

• ORIGINAL ARTICLES • Previous Articles Next Articles

Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity

Jia-Jia Wan^1,2,3, Qiu-Yuan Yin⁴, Mao Sun⁵, Cui-Shan Zhang^1,2,3, Hao-Jing Zang^1,2,4, Pei-Tong Yao^1,2,3, Ming-Rui Yuan^1,2,3, Ding-Kang Chen^1,2,3, Feng Guo^1,2,3, Qun Chen^1,2,4, Bo-Wen Ouyang^1,2,3, Zi-Fei Xu^1,2, Ming-Ming Cao^1,2, Chong-Lin Yang⁴, Xiao-Jiang Hao^1,2,3,6, Ying-Tong Di^1,2,3

1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China;
2. Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China;
3. University of Chinese Academy of Sciences, Beijing, 100049, China;
4. School of Life Sciences, Yunnan University, Kunming, 650091, China;
5. An Shun City People's Hospital, Anshun, 561000, China;
6. Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China

Received:2025-04-12 Accepted:2025-05-17 Online:2025-06-10 Published:2025-08-23
Supported by:
This work was supported by the Yunnan Provincial Science and Technology Department (202203AC100009 to X.J.H, 202201AS070040 and 202302AA310035 to Y.T.D), the National Natural Science Foundation of China (82293683 to X.J.H, and 22177050 to M.M.C.), CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-5-004), the Open Research Fund of Yunnan Characteristic Plant Extraction Laboratory (YKKF2024005), the Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001), and the Reserve Talents of Young and Middle-aged Academic and Technical Leaders in Yunnan Province (Grant NO. 202105AC160044), and Guizhou Provincial Science and Technology Department (QKHJC-ZK[2021]YB557). Authors also thanks the Analytical and Testing Center, Kunming Institute of Botany, Chinese Academy of Sciences for the NMR data.

Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity

1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China;
2. Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China;
3. University of Chinese Academy of Sciences, Beijing, 100049, China;
4. School of Life Sciences, Yunnan University, Kunming, 650091, China;
5. An Shun City People's Hospital, Anshun, 561000, China;
6. Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China

通讯作者: Chong-Lin Yang, E-mail:clyang@ynu.edu.cn;Xiao-Jiang Hao, E-mail:haoxj@mail.kib.ac.cn;Ying-Tong Di, E-mail:diyt@mail.kib.ac.cn
基金资助:
This work was supported by the Yunnan Provincial Science and Technology Department (202203AC100009 to X.J.H, 202201AS070040 and 202302AA310035 to Y.T.D), the National Natural Science Foundation of China (82293683 to X.J.H, and 22177050 to M.M.C.), CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-5-004), the Open Research Fund of Yunnan Characteristic Plant Extraction Laboratory (YKKF2024005), the Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001), and the Reserve Talents of Young and Middle-aged Academic and Technical Leaders in Yunnan Province (Grant NO. 202105AC160044), and Guizhou Provincial Science and Technology Department (QKHJC-ZK[2021]YB557). Authors also thanks the Analytical and Testing Center, Kunming Institute of Botany, Chinese Academy of Sciences for the NMR data.

Abstract

Abstract: The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (2–19). Systematic screening revealed their lysosome-promoting activities, with structure–activity relationship analysis identifying compounds 4 and 18 as superior autophagy inducers. At 20 μM, these derivatives enhanced autophagic flux by 2.45-fold and 2.31-fold versus vehicle control. Moreover, compounds 4 and 18 exhibited a dose-dependent increase in lysosome numbers, promoted TFEB nuclear translocation, and enhanced lysosome-mediated lipid droplet clearance. Western blot analysis further revealed that compounds 4/18 upregulated proteins associated with the autophagy-lysosome system, suggesting their potential as promising autophagy inducers. Mechanistically, molecular docking simulations indicated thier high-affinity binding to PKCδ, which may explain their autophagy-enhancing properties.

Key words: 20-deoxyingenol, SAR, PKCδ, Amino acid

摘要： The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (2–19). Systematic screening revealed their lysosome-promoting activities, with structure–activity relationship analysis identifying compounds 4 and 18 as superior autophagy inducers. At 20 μM, these derivatives enhanced autophagic flux by 2.45-fold and 2.31-fold versus vehicle control. Moreover, compounds 4 and 18 exhibited a dose-dependent increase in lysosome numbers, promoted TFEB nuclear translocation, and enhanced lysosome-mediated lipid droplet clearance. Western blot analysis further revealed that compounds 4/18 upregulated proteins associated with the autophagy-lysosome system, suggesting their potential as promising autophagy inducers. Mechanistically, molecular docking simulations indicated thier high-affinity binding to PKCδ, which may explain their autophagy-enhancing properties.

关键词: 20-deoxyingenol, SAR, PKCδ, Amino acid

Jia-Jia Wan, Qiu-Yuan Yin, Mao Sun, Cui-Shan Zhang, Hao-Jing Zang, Pei-Tong Yao, Ming-Rui Yuan, Ding-Kang Chen, Feng Guo, Qun Chen, Bo-Wen Ouyang, Zi-Fei Xu, Ming-Ming Cao, Chong-Lin Yang, Xiao-Jiang Hao, Ying-Tong Di. Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity[J]. Natural Products and Bioprospecting, 2025, 15(4): 38-38.

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Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity

Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity

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