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Novel Prenylated Indole Alkaloids with Neuroprotection on SH-SY5Y Cells against Oxidative Stress Targeting Keap1–Nrf2

Oxidative stress has been implicated in the etiology of Parkinson’s disease (PD). Molecules non-covalently binding to the Keap1–Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine (1), and asperpendoline (2) with a scarce skeleto...

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Detalles Bibliográficos
Autores principales: Xiao, Xueyang, Tong, Zhou, Zhang, Yuexing, Zhou, Hui, Luo, Mengying, Hu, Tianhui, Hu, Ping, Kong, Luqi, Liu, Zeqin, Yu, Chan, Huang, Zhiyong, Hu, Linzhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8952805/
https://www.ncbi.nlm.nih.gov/pubmed/35323490
http://dx.doi.org/10.3390/md20030191
Descripción
Sumario:Oxidative stress has been implicated in the etiology of Parkinson’s disease (PD). Molecules non-covalently binding to the Keap1–Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine (1), and asperpendoline (2) with a scarce skeleton of pyrimido[1,6-a]indole were discovered from the co-cultivated fungi of Aspergillus ochraceus MCCC 3A00521 and Penicillium sp. HUBU 0120. Compound 2 exhibited potential neuroprotective activity on SH-SY5Y cells against oxidative stress. Molecular mechanism research demonstrated that 2 inhibited Keap1 expression, resulting in the translocation of Nrf2 from the cytoplasm to the nucleus, activating the downstream genes expression of HO-1 and NQO1, leading to the reduction in reactive oxygen species (ROS) and the augment of glutathione. Molecular docking and dynamic simulation analyses manifested that 2 interacted with Keap1 (PDB ID: 1X2R) via forming typical hydrogen and hydrophobic bonds with residues and presented less fluctuation of RMSD and RMSF during a natural physiological condition.