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.

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].