应用天然产物 ›› 2025, Vol. 15 ›› Issue (4): 38-38.DOI: 10.1007/s13659-025-00522-x
Jia-Jia Wan1,2,3, Qiu-Yuan Yin4, Mao Sun5, Cui-Shan Zhang1,2,3, Hao-Jing Zang1,2,4, Pei-Tong Yao1,2,3, Ming-Rui Yuan1,2,3, Ding-Kang Chen1,2,3, Feng Guo1,2,3, Qun Chen1,2,4, Bo-Wen Ouyang1,2,3, Zi-Fei Xu1,2, Ming-Ming Cao1,2, Chong-Lin Yang4, Xiao-Jiang Hao1,2,3,6, Ying-Tong Di1,2,3
Jia-Jia Wan1,2,3, Qiu-Yuan Yin4, Mao Sun5, Cui-Shan Zhang1,2,3, Hao-Jing Zang1,2,4, Pei-Tong Yao1,2,3, Ming-Rui Yuan1,2,3, Ding-Kang Chen1,2,3, Feng Guo1,2,3, Qun Chen1,2,4, Bo-Wen Ouyang1,2,3, Zi-Fei Xu1,2, Ming-Ming Cao1,2, Chong-Lin Yang4, Xiao-Jiang Hao1,2,3,6, Ying-Tong Di1,2,3
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.