Synthesis and biological evaluation of 2′-hydroxychalcone derivatives as AMPK activators
Issued Date
2024-02-01
Resource Type
ISSN
00452068
eISSN
10902120
Scopus ID
2-s2.0-85180605943
Pubmed ID
38141328
Journal Title
Bioorganic Chemistry
Volume
143
Rights Holder(s)
SCOPUS
Bibliographic Citation
Bioorganic Chemistry Vol.143 (2024)
Suggested Citation
Vu Nguyen D., Muanprasat C., Kaewin S., Hengphasatporn K., Shigeta Y., Rungrotmongkol T., Chavasiri W. Synthesis and biological evaluation of 2′-hydroxychalcone derivatives as AMPK activators. Bioorganic Chemistry Vol.143 (2024). doi:10.1016/j.bioorg.2023.107048 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/95743
Title
Synthesis and biological evaluation of 2′-hydroxychalcone derivatives as AMPK activators
Corresponding Author(s)
Other Contributor(s)
Abstract
A series of 2′-hydroxychalcone derivatives with various substituents on B-ring were synthesized and evaluated for AMP-activated protein kinase (AMPK) activation activity in podocyte cells. The results displayed that hydroxy, methoxy and methylenedioxy groups on B-ring could enhance the activitiy better than O-saturated alkyl, O-unsaturated alkyl or other alkoxy groups. Compounds 27 and 29 possess the highest fold change of 2.48 and 2.73, respectively, which were higher than those of reference compound (8) (1.28) and metformin (1.88). Compounds 27 and 29 were then subjected to a concentration–response study to obtain the EC50 values of 2.0 and 4.8 µM, respectively and MTT assays also showed that cell viability was not influenced by the exposure of podocytes to compounds 27 and 29 at concentrations up to 50 μM. In addition, compound 27 was proved to activate AMPK via calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-dependent pathway without affecting intracellular calcium levels. The computational study showed that the potent compounds exhibited stronger ligand-binding strength to CaMKKβ, particularly compounds 27 (−8.4 kcal/mol) and 29 (−8.0 kcal/mol), compared to compound 8 (-7.5 kcal/mol). Fragment molecular orbital (FMO) calculation demonstrated that compound 27 was superior to compound 29 due to the presence of methyl group, which amplified the binding by hydrophobic interactions. Therefore, compound 27 would represent a promising AMPK activator for further investigation of the treatment of diabetes and diabetic nephropathy.