The potential of Rhein's aromatic amines for Parkinson's disease prevention and treatment: α-Synuclein aggregation inhibition and disaggregation of preformed fibers.

Autor: Zhang W; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Liu W; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Zhao YD; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Xing LZ; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China., Xu J; Department of Pharmacology, School of Basic Medical Science, Zhengzhou University, Kexue Road 100, 450001 Zhengzhou, China; Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Kexue Road 100, 450001 Zhengzhou, China. Electronic address: xuji@zzu.edu.cn., Li RJ; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China. Electronic address: liruijun@zzu.edu.cn., Zhang YX; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China. Electronic address: zhangyx@zzu.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Jan 01; Vol. 97, pp. 129564. Date of Electronic Publication: 2023 Nov 22.
DOI: 10.1016/j.bmcl.2023.129564
Abstrakt: The aggregation of α-Syn is a pivotal mechanism in Parkinson's disease (PD). Effectively maintaining α-Syn proteostasis involves both inhibiting its aggregation and promoting disaggregation. In this study, we developed a series of aromatic amide derivatives based on Rhein. Two of these compounds, 4,5-dihydroxy-N-(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a5) and 4,5-dihydroxy-N-(2-hydroxy-4-chlorophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a8), exhibited good binding affinities to α-Syn residues, demonstrating promising inhibitory activity against α-Syn aggregation in vitro, with low IC 50 values (1.35 and 1.08 μM, respectivly). These inhibitors acted throughout the entire aggregation process by stabilizing α-Syn's conformation and preventing the formation of β-sheet aggregates. They also effectively disassembled preformed α-Syn oligomers and fibrils. Preliminary mechanistic insights indicated that they bound to the specific domain within fibrils, inducing fibril instability, collapse, and the formation of smaller aggregates and monomeric α-Syn units. This research underscores the therapeutic potential of Rhein's aromatic amides in targeting α-Syn aggregation for PD treatment and suggests broader applications in managing and preventing neurodegenerative diseases.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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