Discovery of novel paeonol-based derivatives against skin inflammation in vitro and in vivo

Jing Wu; Ren De Zhu; Guo Min Cao; Jun Cheng Du; Xin Liu; Liang Zhuo Diao; Zhao Yan Zhang; Yang Sheng Hu; Xin Hua Liu; Jing Bo Shi

doi:10.1080/14756366.2022.2043852

Discovery of novel paeonol-based derivatives against skin inflammation in vitro and in vivo

J Enzyme Inhib Med Chem. 2022 Dec;37(1):817-831. doi: 10.1080/14756366.2022.2043852.

Authors

Jing Wu^{1

2}, Ren De Zhu^{1

2}, Guo Min Cao^{1

2}, Jun Cheng Du^{1

2}, Xin Liu³, Liang Zhuo Diao^{1

2}, Zhao Yan Zhang^{1

2}, Yang Sheng Hu^{1

2

4}, Xin Hua Liu^{1

2}, Jing Bo Shi^{1

2}

Affiliations

¹ School of Pharmacy, Anhui Medical University, Hefei, P. R. China.
² Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, P. R. China.
³ Department of Clinical Medicine, Second Clinical Medical College, Anhui Medical University, Hefei, P. R. China.
⁴ Department of Medicine, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, P. R. China.

Abstract

T-LAK-cell-originated protein kinase (TOPK), a novel member of the mitogen-activated protein kinase family, is considered an effective therapeutic target for skin inflammation. In this study, a series (A - D) of paeonol derivatives was designed and synthesised using a fragment growing approach, and their anti-inflammatory activities against lipopolysaccharide (LPS)-induced nitric oxide production in RAW264.7 cells were tested. Among them, compound B12 yielded the best results (IC₅₀ = 2.14 μM) with low toxicity (IC₅₀ > 50 µM). Preliminary mechanistic studies indicated that this compound could inhibit the TOPK-p38/JNK signalling pathway and phosphorylate downstream related proteins. A murine psoriasis-like skin inflammation model was used to determine its therapeutic effect.

Keywords: T-LAK-cell-originated protein kinase; anti-inflammatory; design; paeonol derivatives; synthesis.

MeSH terms

Acetophenones / chemical synthesis
Acetophenones / chemistry
Acetophenones / pharmacology*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Cell Line
Cell Proliferation / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Discovery*
Female
Humans
Inflammation / drug therapy*
Inflammation / metabolism
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases / metabolism
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Mice
Mice, Inbred BALB C
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases / metabolism
Molecular Structure
Nitric Oxide / antagonists & inhibitors
Nitric Oxide / biosynthesis
Signal Transduction / drug effects
Skin / drug effects*
Skin / metabolism
Structure-Activity Relationship
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Acetophenones
Anti-Inflammatory Agents, Non-Steroidal
Lipopolysaccharides
Nitric Oxide
paeonol
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
PDZ-binding kinase
TOPK protein, mouse

Grants and funding

This work was supported by the National Natural Science Funding of China [21977001], National College Students’ innovation and entrepreneurship training program [202010366047], Pharmaceutical innovative fund [YXCX202102].