SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway.

Abstract

Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a Kd of 0.87 μM was found to be less toxic than celastrol and could be a hit molecule for further optimization.

• Authors: Ziwen Chen, Duo Zhang, Siwei Yan, Chaochao Hu, Zhenfei Huang, Zhuoer Li, Shuangzhou Peng, Xiaotong Li, Yi Zhu, Hongyu Yu, Baohuan Lian, Qi Kang, Mingyu Li, Zhiping Zeng, Xiao-Kun Zhang, Ying Su
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 177 Pg. 171-187 (Sep 01 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31132532 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• NR4A1 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 1
• PSMD2 protein, human
• Pentacyclic Triterpenes
• SQSTM1 protein, human
• Sequestosome-1 Protein
• TNF Receptor-Associated Factor 2
• Triterpenes
• celastrol

Topics

• Animals
• Anti-Inflammatory Agents (chemical synthesis, metabolism, pharmacology, toxicity)
• Binding Sites
• Drug Design
• Hep G2 Cells
• Humans
• Molecular Docking Simulation
• Molecular Structure
• Nuclear Receptor Subfamily 4, Group A, Member 1 (antagonists & inhibitors, chemistry, metabolism)
• Pentacyclic Triterpenes
• Protein Binding (drug effects)
• Sequestosome-1 Protein (metabolism)
• Structure-Activity Relationship
• TNF Receptor-Associated Factor 2 (metabolism)
• Triterpenes (chemical synthesis, metabolism, pharmacology, toxicity)
• Zebrafish