PUBLICATION
Synthesis and in vivo screening of isosteviol derivatives as new cardioprotective agents
- Authors
- Zhang, H., Liu, B., Xu, G., Xu, C., Ou, E., Liu, J., Sun, X., Zhao, Y.
- ID
- ZDB-PUB-210418-9
- Date
- 2021
- Source
- European Journal of Medicinal Chemistry 219: 113396 (Journal)
- Registered Authors
- Keywords
- Cardioprotective activity, In vivo screening, Isosteviol, Structure-activity relationship (SAR), Zebrafish
- MeSH Terms
-
- Animals
- Zebrafish/growth & development
- Diterpenes, Kaurane/chemistry*
- Diterpenes, Kaurane/pharmacology
- Diterpenes, Kaurane/therapeutic use
- Membrane Potential, Mitochondrial/drug effects
- Apoptosis/drug effects
- Doxorubicin/toxicity
- Heart/drug effects
- Heart/physiology
- Rats
- Cardiomyopathies/drug therapy
- Cardiomyopathies/pathology
- Cardiotonic Agents/chemical synthesis*
- Cardiotonic Agents/pharmacology
- Cardiotonic Agents/therapeutic use
- Cell Survival/drug effects
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/physiology
- Reactive Oxygen Species/metabolism
- Structure-Activity Relationship
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- PubMed
- 33862515 Full text @ Eur. J. Med. Chem.
Citation
Zhang, H., Liu, B., Xu, G., Xu, C., Ou, E., Liu, J., Sun, X., Zhao, Y. (2021) Synthesis and in vivo screening of isosteviol derivatives as new cardioprotective agents. European Journal of Medicinal Chemistry. 219:113396.
Abstract
Isosteviol, an ent-beyerane diterpenoid, has been repeatedly reported to possess potent cardioprotective activity. With the aim of discovering new cardioprotective derivatives from isosteviol, 47 compounds, including 40 new ones, were synthesized and evaluated in vivo using the easy-handling and efficient zebrafish model. The structure-activity relationship of this type of compounds was thus discussed. Of these compounds, new derivative 15d exhibited the most pronounced efficacy in vivo. Our results indicated that 15d could effectively prevent the doxorubicin-induced morphological distortions and cardiac dysfunction in zebrafish. Its cardioprotective activity is much better than that of isosteviol, and Levosimendan in zebrafish model. The molecular mechanism underlying in H9c2 cells indicated that 15d protected cardiomyocyte death and damage through inhibiting the reactive oxygen species overproduction, restoring the mitochondrial membrane potential and maintaining morphology of mitochondrial. Thus, 15d merits further development as a potential cardioprotective clinical trial candidate. The present study is a successful example to combine synthesis, structure-activity relationship study and in vivo screening to effectively discover new cardioprotective agents from isosteviol.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping