Hybrids of polyphenolic/quinone acids, the potential preventive and therapeutic drugs for PD: Disaggregate α-Syn fibrils, inhibit inclusions, and repair damaged neurons in mice.

Autor: Lü MH; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China; Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China., Wang ZP; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China., Xing LZ; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China., Zhang W; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China., Han F; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China., Huang GL; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China., Liu W; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China., Zhang YX; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, Zhengzhou, 450052, China. Electronic address: zhangyx@zzu.edu.cn., Xu J; School of Basic Medical Science, Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Kexue Road 100, Zhengzhou, 45000, China. Electronic address: xuji@zzu.edu.cn., Cui J; Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China. Electronic address: jinquan_cui@163.com.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Mar 05; Vol. 249, pp. 115122. Date of Electronic Publication: 2023 Jan 18.
DOI: 10.1016/j.ejmech.2023.115122
Abstrakt: Neurotoxic α-Syn fibers, the main components of Lewy bodies, play a key role in the development of PD characterized by a progressive loss of dopaminergic neurons. Here, we designed and synthesized the hybrids of polyphenolic/quinone acids. The candidate compounds showed high α-Syn aggregation inhibitory activities in vitro with IC 50 down to 1.6 μM. The inhibition went through the aggregation process by stabilizing the conformation of α-Syn proteostasis and preventing β-sheets aggregation, especially in the lag phase. Furthermore, the candidate drugs could disintegrate the preformed varisized aggregates into pony-size aggregates and functional monomers and continually inhibit the re-aggregation. The activities of anti-aggregation and aggregates depolymerization result in the reduction of inclusions in neuron cells. The candidate drugs also show high anti-oxidation and low cytotoxicity. They finally repair the damaged neurons in 6-OHDA-lesioned C57 mice and significantly improve PD-like symptoms of the PD model mice. The hybrids are promising molecules for PD prevention and therapy.© 2022 Elsevier Masson SAS. All rights reserved.
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 Masson SAS. All rights reserved.)
Databáze: MEDLINE
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