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Synthesis and biological evaluation of 2'-hydroxychalcone derivatives as AMPK activators. | LitMetric

Synthesis and biological evaluation of 2'-hydroxychalcone derivatives as AMPK activators.

Bioorg Chem

Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand. Electronic address:

Published: February 2024

AI Article Synopsis

  • A series of 2'-hydroxychalcone derivatives were created and tested for their ability to activate AMPK in podocyte cells, with specific substituents on the B-ring improving activity.
  • Compounds 27 and 29 showed the highest AMPK activation levels compared to a reference compound and metformin, and were safe for podocyte cells at concentrations up to 50 µM.
  • Compound 27 was confirmed to activate AMPK through a specific pathway and exhibited strong binding to a protein kinase, marking it as a potential candidate for diabetes and diabetic nephropathy treatment.

Article 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 EC 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.

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Source
http://dx.doi.org/10.1016/j.bioorg.2023.107048DOI Listing

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