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

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

  • Bioorg Med Chem Lett. 2024 Jan 1:97:129564. doi: 10.1016/j.bmcl.2023.129564.
Wei Zhang 1 Wei Liu 1 Ya-Dong Zhao 1 Li-Zi Xing 1 Ji Xu 2 Rui-Jun Li 3 Yun-Xiao Zhang 4
Affiliations

Affiliations

  • 1 Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China.
  • 2 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.
  • 3 Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China. Electronic address: liruijun@zzu.edu.cn.
  • 4 Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052 Zhengzhou, China. Electronic address: zhangyx@zzu.edu.cn.
Abstract

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 IC50 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.

Keywords

Aromatic amide derivatives of Rhein; Mechanism; Synthesis; α-Syn aggregation inhibitor Disaggregation.

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