Synthesis and discovery of ω-3 polyunsaturated fatty acid- alkanolamine (PUFA-AA) derivatives as anti-inflammatory agents targeting Nur77

Hua Fang; Jianyu Zhang; Mingtao Ao; Fengming He; Weizhu Chen; Yuqing Qian; Yuxiang Zhang; Yang Xu; Meijuan Fang

doi:10.1016/j.bioorg.2020.104456

Synthesis and discovery of ω-3 polyunsaturated fatty acid- alkanolamine (PUFA-AA) derivatives as anti-inflammatory agents targeting Nur77

Bioorg Chem. 2020 Dec:105:104456. doi: 10.1016/j.bioorg.2020.104456. Epub 2020 Nov 8.

Authors

Hua Fang¹, Jianyu Zhang², Mingtao Ao², Fengming He², Weizhu Chen¹, Yuqing Qian², Yuxiang Zhang², Yang Xu³, Meijuan Fang⁴

Affiliations

¹ Third Institute of Oceanography, Ministry of Natural Resources, Technical Innovation Center for Utilization of Marine Biological Resources, Ministry of Natural Resources, Xiamen 361005, China.
² Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
³ Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: xu_yang@xmu.edu.cn.
⁴ Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: fangmj@xmu.edu.cn.

PMID: 33217634
DOI: 10.1016/j.bioorg.2020.104456

Abstract

In this work, three series of ω-3 polyunsaturated fatty acid-alkanolamine derivatives (PUFA-AAs) were synthesized, characterized and their anti-inflammatory activity in vivo was evaluated. Compounds 4a, 4f, and 4k exhibited marked anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. The most promising compound 4k dose-dependently suppressed the cytokines with IC₅₀ values in the low micromolar range. Further, 4k exhibited potential in vitro Nur77-binding affinity (K_d = 6.99 × 10^-6 M) which is consistent with the result of docking studies. Next, the anti-inflammatory mechanism of 4k was found to be through NF-κB signal pathway in a Nur77-dependent manner. Moreover, we also observed 4k significantly inhibited LPS-induced expression of cytokines (IL-6, TNF-α, and IL-1β) through suppressing NF-κB activation and attenuated LPS-induced inflammation in mouse acute lung injury (ALI) model. In conclusion, the study strongly suggests that the PUFA-AA derivatives can be particularly as new Nur77 mediators for further treatment in inflammatory diseases.

Keywords: Acute lung injury; Anti-inflammatory activity; Molecular docking; Nur77; ω-3 polyunsaturated fatty acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry*
Animals
Anti-Inflammatory Agents / chemical synthesis*
Anti-Inflammatory Agents / pharmacology
Cytokines / metabolism
Disease Models, Animal
Drug Design
Enzyme Activation / drug effects
Fatty Acids, Unsaturated / chemical synthesis*
Fatty Acids, Unsaturated / pharmacology
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
NF-kappa B / metabolism
Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
RAW 264.7 Cells
Signal Transduction

Substances

Amines
Anti-Inflammatory Agents
Cytokines
Fatty Acids, Unsaturated
NF-kappa B
Nuclear Receptor Subfamily 4, Group A, Member 1