Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA(1) and hA(3) Adenosine Receptor

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): hA(1), hA(2A), hA(2B), and hA(3). Both hA(1) and hA(3) 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 hA(1) and hA(3) AR, while 9c showed the highest binding affinity to hA(1) 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 hA(1) and hA(3) AR were predicted by a molecular docking study.