Synthesis, biological evaluation and structure-activity relationship studies of hederacolchiside E and its derivatives as potential anti-Alzheimer agents

Hui-Ning Li; Yang Liu; Zuo-Peng Zhang; Zhi-Peng Wang; Jing-Zheng Hao; Feng-Ran Li; Zhan-Fang Fan; Li-Bo Zou; Mao-Sheng Cheng

doi:10.1016/j.ejmech.2017.11.040

Synthesis, biological evaluation and structure-activity relationship studies of hederacolchiside E and its derivatives as potential anti-Alzheimer agents

Eur J Med Chem. 2018 Jan 1:143:376-389. doi: 10.1016/j.ejmech.2017.11.040. Epub 2017 Nov 21.

Authors

Hui-Ning Li¹, Yang Liu², Zuo-Peng Zhang¹, Zhi-Peng Wang¹, Jing-Zheng Hao¹, Feng-Ran Li¹, Zhan-Fang Fan¹, Li-Bo Zou³, Mao-Sheng Cheng⁴

Affiliations

¹ Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: y.liu@syphu.edu.cn.
³ School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁴ Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: mscheng@syphu.edu.cn.

PMID: 29202401
DOI: 10.1016/j.ejmech.2017.11.040

Abstract

Inspired by the previously reported neuroprotective activity of hederacolchiside E (1), we synthesized hederacolchiside E for the first time along with eleven of its derivatives. The neuroprotective effects of these compounds were further evaluated against H₂O₂- and Aβ_1-42-induced injury using cell-based assays. The derivatives showed obvious differences in activity due to structural variations, and two of them exhibited better neuroprotective effects than 1 in the Aβ_1-42-induced injury model. Compound 7 was the most active derivative and had a relatively simple chemical structure. Moreover, 1 and 7 can significantly reduce the release of lactate dehydrogenase (LDH), level of intracellular reactive oxygen species (ROS) and extent of malondialdehyde (MDA) increase resulting from Aβ_1-42 treatment, which demonstrated that these kinds of compounds show neuroprotective effects in Alzheimer's disease (AD) models via modulating oxidative stress. Compound 7 could be used as promising lead for the development of a new type of neuroprotective agent against AD.

Keywords: Alzheimer's disease; Antioxidation; Hederacolchiside E; Neuroprotective effects; Structure-activity relationship.

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism
Animals
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Hydrogen Peroxide / antagonists & inhibitors
Hydrogen Peroxide / pharmacology
L-Lactate Dehydrogenase / antagonists & inhibitors
L-Lactate Dehydrogenase / metabolism
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
PC12 Cells
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism
Rats
Reactive Oxygen Species / analysis
Reactive Oxygen Species / metabolism
Saponins / chemical synthesis
Saponins / chemistry
Saponins / pharmacology*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Neuroprotective Agents
Peptide Fragments
Reactive Oxygen Species
Saponins
amyloid beta-protein (1-42)
hederacolchiside E
Hydrogen Peroxide
L-Lactate Dehydrogenase