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

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

doi:10.1007/s13659-025-00522-x

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

Nat Prod Bioprospect. 2025 Jun 10;15(1):38. doi: 10.1007/s13659-025-00522-x.

Authors

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 Yang⁶, Xiao-Jiang Hao^{7

8

9

10}, Ying-Tong Di^{11

12

13}

Affiliations

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 School of Life Sciences, Yunnan University, Kunming, 650091, China. clyang@ynu.edu.cn.
⁷ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. haoxj@mail.kib.ac.cn.
⁸ Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China. haoxj@mail.kib.ac.cn.
⁹ University of Chinese Academy of Sciences, Beijing, 100049, China. haoxj@mail.kib.ac.cn.
¹⁰ Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing, 100730, China. haoxj@mail.kib.ac.cn.
¹¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China. diyt@mail.kib.ac.cn.
¹² Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China. diyt@mail.kib.ac.cn.
¹³ University of Chinese Academy of Sciences, Beijing, 100049, China. diyt@mail.kib.ac.cn.

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.

Keywords: 20-deoxyingenol; Amino acid; PKCδ; SAR.

Abstract

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