Bis-chalcone polyphenols with potential preventive and therapeutic effects on PD: Design, synthesis and in vitro disaggregation activity against α-synuclein oligomers and fibrils

Eur J Med Chem. 2022 Jun 16;239:114529. doi: 10.1016/j.ejmech.2022.114529. Online ahead of print.ABSTRACTα-Syn fibrils, which are neurotoxic, play a key role in the development of PD. Maintaining α-Syn proteostasis by suitable molecule ligands is an effective approach to prevent aggregation. Disintegrating the existed oligomers and fibrils into individual α-Syn by small molecular compounds is a more efficient way to treat PD. This work designed and synthesized two series of bis-chalcone polyphenol compounds, which possess a sheet-like conjugated skeleton with stronger H-bonding, π-stacking, and hydrophobic interaction with α-Syn protein residues. Some compounds have shown high α-Syn aggregation inhibitory activities in vitro with IC50 down to 0.64 μM. The inhibition goes throughout the aggregation process from the lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing β-sheets aggregation, especially in the lag phase. In addition, the inhibitors present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the β-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril and yielding a complex system with aggregates of different sizes and monomers. The inhibitors, which could penetrate the blood-brain barrier, are expected to develop into the drug candidates ...

Source: European Journal of Medicinal Chemistry - June 21, 2022 Category: Chemistry Authors: Bing Jiang Feng Han Ming-Huan L ü Zhen-Ping Wang Wei Liu Yun-Xiao Zhang Ji Xu Rui-Jun Li Source Type: research