Molecules (Jun 2022)

Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA<sub>1</sub> and hA<sub>3</sub> Adenosine Receptor

  • Sujin Park,
  • Yujin Ahn,
  • Yongchan Kim,
  • Eun Joo Roh,
  • Yoonji Lee,
  • Chaebin Han,
  • Hee Min Yoo,
  • Jinha Yu

DOI
https://doi.org/10.3390/molecules27134016
Journal volume & issue
Vol. 27, no. 13
p. 4016

Abstract

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Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study.

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