Flavonoid Derivatives Targeting BCR-ABL Kinase: Semisynthesis, Molecular Dynamic Simulations and Enzymatic Inhibition

Curr Top Med Chem. 2021;21(22):1999-2017. doi: 10.2174/1568026621666210705170047.

Abstract

Background: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics.

Objective: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors.

Methods: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase.

Results: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k).

Conclusion: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.

Keywords: 6-hydroxy-flavanone skeleton.; BCR-ABL kinase inhibitors; Chronic myeloid leukemia; Semisynthesis; Triazole; Williamson synthesis.

MeSH terms

  • Flavonoids / chemical synthesis*
  • Flavonoids / pharmacology*
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Molecular Dynamics Simulation*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Flavonoids
  • Protein Kinase Inhibitors
  • Fusion Proteins, bcr-abl