Subtle Structural Changes across the Boundary between A<sub>2A</sub>R/A<sub>2B</sub>R Dual Antagonism and A<sub>2B</sub>R Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives
Haojie Wang, Xinyu Yang, Yan Li, Shuyin Ze, Bo Feng, Yuan Weng, Aoqi Gao, Gaojie Song, Mingyao Liu, Qiong Xie, Yonghui Wang, Weiqiang Lü
Abstract
Aberrantly elevated adenosine in the tumor microenvironment exerts its immunosuppressive functions through adenosine receptors A 2A R and A 2B R. Antagonism of A 2A R and A 2B R has the potential to suppress tumor growth. Herein, we report a systemic assessment of the effects of an indole modification at position 4, 5, 6, or 7 on both A 2A R/A 2B R activity and selectivity of novel 2-aminopyrimidine compounds. Substituting indole at the 4-/5-position produced potent A 2A R/A 2B R dual antagonism, whereas the 6-position of indole substitution gave highly selective A 2B R antagonism. Molecular dynamics simulation showed that the 5-cyano compound 7ai had a lower binding free energy than the 6-cyano compound 7aj due to water-bridged hydrogen bond interactions with E169 or F168 in A 2A R. Of note, dual A 2A R/A 2B R antagonism by compound 7ai can profoundly promote the activation and cytotoxic function of T cells. This work provided a strategy for obtaining novel dual A 2A R/A 2B R or A 2B R antagonists by fine-tuning structural modification.