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Molecular hybridization method for obtaining paeonol-based fibrate derivatives with potent lipid-lowering and hepatoprotective activity

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Abstract

Molecular hybridization method was applied to design and synthesize a series of target compounds paeonol-based fibrate derivatives. The target compound was screened using a Triton WR-1339 induced hyperlipidemia mouse model, and compound T9 was found to have good lipid-lowering activity. The dose-dependent study of its lipid-lowering activity was also conducted. To further evaluate the lipid-lowering activity of compound T9, a hyperlipidemic mouse model induced by high fat emulsion can be used. The findings of the research illustrate that T9 is capable of significantly decreasing blood lipid levels, including TG, TC, LDL-C, and increasing HDL-C. The results of liver tissue oil red O staining and HE staining demonstrated that T9 improved the hepatic lipid accumulation, thus decreasing AST and ALT levels and protecting against hyperlipidemic liver injury. Studies into the lipid-lowering effect of T9 have indicated that it can upregulate PPAR-α protein expression in liver tissue, while simultaneously decreasing the expression of HMG-CoA protein. T9 was further demonstrated to possess antioxidant properties, as evidenced by an increase in SOD and a decrease in MDA, as well as anti-inflammatory effects, demonstrated by a decrease in TNF-α, IL-1β, and IL-6, thus confirming its potential as a hypolipidemia and hepatoprotective agent.

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Abbreviations

ALT:

alanine aminotransferase

AST:

aspartate transaminase

CF:

clofibrate

13C NMR:

13C-nuclear magnetic resonance

DMAP:

4-Dimethylaminopyridine

DMF:

N,N-dimethylformamide

EDCI:

1-(3-dimethylaminopropyl) -3-ethylcarbodiimide

MS:

mass spectrometry

HDL-C:

high density lipoprotein cholesterol

HMG-CoA:

hydroxymethylglutaryl coenzyme A

1H NMR:

1H-nuclear magnetic resonance

IL-1β:

interleukin-1β

IL-6:

interleukin-6

LDL-C:

low density lipoprotein cholesterol

MDA:

malondialdehyde

PPAR-α:

peroxisome proliferator-activated receptor-α

SOD:

superoxide dismutase

TC:

total cholesterol

TG:

triglycerides

TNF-α:

tumor necrosis factor-α

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Acknowledgements

This study was supported by Shaanxi University of Traditional Chinese Medicine Student Innovation and Entrepreneurship Training Program Project (No. 202210716107). Sci-Tech Innovation Talent System Construction Program of Shaanxi University of Chinese Medicine (No. 2023-CXTD-05). Shaanxi Special Support Plan Talent Project. Shaanxi Provincial Administration of Traditional Chinese Medicine “Double Chain Integration” Young and middle-aged Scientific Research and Innovation Team Project (No. 2022-SLRH-YQ-008). Shaanxi Province key research and development plan project (No. 2024SF-YBXM-496).

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Authors and Affiliations

  1. College of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an-xianyang New Ecomic Zone, Xi’an, 7T9046, China

    Lina Quan, Ying Guo, Siyao Wang, Mengfei Sun, Yan Pang, Chunli Cui, Peifeng Wei & Yundong Xie

  2. Department of Life Science and Medicine, College of Life Science, Northwest University, Xi’an, 710069, China

    Jinrui Wang

  3. State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China

    Jinlian Wei

  4. The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang, China

    Peifeng Wei

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  1. Lina Quan
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Quan, L., Guo, Y., Wang, S. et al. Molecular hybridization method for obtaining paeonol-based fibrate derivatives with potent lipid-lowering and hepatoprotective activity. Med Chem Res 33, 796–810 (2024). https://doi.org/10.1007/s00044-024-03214-2

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