Synthesis and cytotoxic activity of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group as the A-ring or B-ring

Bioorg Chem. 2020 Jan:94:103346. doi: 10.1016/j.bioorg.2019.103346. Epub 2019 Oct 10.

Abstract

Many natural or synthetic chalcones have potential anti-tumor activity. Here, we synthesized two series of chalcone analogues containing a thieno[2,3-d]pyrimidin-2-yl group and evaluated for their cytotoxic activity towards cultured human lung cancer A549 and colorectal HCT-116 cells. Among them, compound 8d was the most cytotoxic against HCT-116 cells, with an IC50 value of 2.65 μM. Analyses of the phenotypic changes induced by this compound found a dose-dependent accumulation of HCT-116 cells in sub-G1 phase, indicating that compound 8d might induce apoptosis. Furthermore, we found that 8d triggered mitochondrial membrane potential depolarization, promoted reactive oxygen species formation in HCT-116 cells, and increased the percentage of early and late apoptotic cells. Finally, immunoblotting indicated that 8d increased PARP-1 and caspases 3, 7 and 9 cleavage. These data suggest that compound 8d induces apoptosis via the mitochondrial death pathway.

Keywords: Apoptosis; Chalcone analogue; Cytotoxicity; Mitochondrial death pathway; Thieno[2,3-d]pyrimidin-4(3H)-one.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Chalcones / chemical synthesis*
  • Chalcones / chemistry
  • Chalcones / pharmacology*
  • HCT116 Cells
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects
  • Oxidative Stress / drug effects
  • Pyrimidines / chemistry*

Substances

  • Antineoplastic Agents
  • Chalcones
  • Pyrimidines