PUBLICATION
SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway
- Authors
- Chen, Z., Zhang, D., Yan, S., Hu, C., Huang, Z., Li, Z., Peng, S., Li, X., Zhu, Y., Yu, H., Lian, B., Kang, Q., Li, M., Zeng, Z., Zhang, X.K., Su, Y.
- ID
- ZDB-PUB-190726-11
- Date
- 2019
- Source
- European Journal of Medicinal Chemistry 177: 171-187 (Journal)
- Registered Authors
- Li, Mingyu
- Keywords
- Anti-inflammatory, Celastrol, Celastrol derivatives, Nur77, SAR
- MeSH Terms
-
- Animals
- Anti-Inflammatory Agents/chemical synthesis
- Anti-Inflammatory Agents/metabolism
- Anti-Inflammatory Agents/pharmacology*
- Anti-Inflammatory Agents/toxicity
- Binding Sites
- Drug Design
- Hep G2 Cells
- Humans
- Molecular Docking Simulation
- Molecular Structure
- Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors*
- Nuclear Receptor Subfamily 4, Group A, Member 1/chemistry
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Protein Binding/drug effects
- Sequestosome-1 Protein/metabolism
- Structure-Activity Relationship
- TNF Receptor-Associated Factor 2/metabolism
- Triterpenes/chemical synthesis
- Triterpenes/metabolism
- Triterpenes/pharmacology*
- Triterpenes/toxicity
- Zebrafish
- PubMed
- 31132532 Full text @ Eur. J. Med. Chem.
Citation
Chen, Z., Zhang, D., Yan, S., Hu, C., Huang, Z., Li, Z., Peng, S., Li, X., Zhu, Y., Yu, H., Lian, B., Kang, Q., Li, M., Zeng, Z., Zhang, X.K., Su, Y. (2019) SAR study of celastrol analogs targeting Nur77-mediated inflammatory pathway. European Journal of Medicinal Chemistry. 177:171-187.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping