PUBLICATION
Design, synthesis and biological evaluation of novel pyxinol derivatives with anti-heart failure activity
- Authors
- Liu, J., Liu, Y., Yu, H., Zhang, Y., Hsu, A.C., Zhang, M., Gou, Y., Sun, W., Wang, F., Li, P., Liu, J.
- ID
- ZDB-PUB-210101-15
- Date
- 2021
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 133: 111050 (Journal)
- Registered Authors
- Keywords
- ACE inhibition, Fatty acid esters, Heart failure, Metabolomics, Molecular docking, Pyxinol
- MeSH Terms
-
- Angiotensin-Converting Enzyme Inhibitors/chemical synthesis*
- Angiotensin-Converting Enzyme Inhibitors/pharmacology*
- Angiotensin-Converting Enzyme Inhibitors/toxicity
- Animals
- Cell Line
- Disease Models, Animal
- Drug Design*
- Energy Metabolism/drug effects*
- Heart Failure/chemically induced
- Heart Failure/drug therapy*
- Heart Failure/metabolism
- Heart Failure/physiopathology
- Metabolomics
- Molecular Docking Simulation
- Molecular Structure
- Myocardial Contraction/drug effects
- Myocytes, Cardiac/drug effects*
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Rats
- Structure-Activity Relationship
- Ventricular Function/drug effects*
- Verapamil
- Zebrafish
- PubMed
- 33378957 Full text @ Biomed. Pharmacother.
Citation
Liu, J., Liu, Y., Yu, H., Zhang, Y., Hsu, A.C., Zhang, M., Gou, Y., Sun, W., Wang, F., Li, P., Liu, J. (2021) Design, synthesis and biological evaluation of novel pyxinol derivatives with anti-heart failure activity. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 133:111050.
Abstract
Heart failure (HF) is an important and leading cause of substantial morbidity and mortality globally. The angiotensin-converting enzymatic (ACE) is the causative source for congestive heart failure. Natural products and its derivatives play a vital role in drug discovery and development owing to their efficacy and low toxicity. Pyxinol is a potent natural agent for cardiovascular disease. Thus we investigated the effect on ACE and HF of pyxinol derivatives. We designed and synthesized 32 novel fatty acid ester derivatives of pyxinol via esterification. Among them, compounds 2e (IC50=105 nM) and 3b (IC50=114 nM) displayed excellent ACE inhibitory activity in vitro, and exhibited non-toxic to H9c2 cells. The interactions between ACE and compounds were predicted by molecular docking respectively. In verapamil-induced zebrafish HF model, the activity assay showed that these two derivatives could improve cardiovascular physiological indexes including heart beats, venous congestion, heart dilation, cardiac output, ejection fraction and fractional shortening in a dose-dependent manner. A UPLC-QTOF-MS-based serum metabolomics approach was applied to explore the latent mechanism. A total of 25 differentiated metabolites and 8 perturbed metabolic pathways were identified. These results indicated that pyxinol fatty acid ester derivatives 2e and 3b might be considered as potent drug candidates against heart failure and deserved further research and development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping