Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives,Journal of Medicinal Chemistry

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Subtle Structural Changes across the Boundary between A2AR/A2BR Dual Antagonism and A2BR Antagonism: A Novel Class of 2-Aminopyrimidine-Based Derivatives
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-14 , DOI: 10.1021/acs.jmedchem.4c00250
Haojie Wang ₁ , Xinyu Yang ₂ , Yan Li ₁ , Shuyin Ze ₃ , Bo Feng ₄ , Yuan Weng ₃ , Aoqi Gao ₃ , Gaojie Song ₃ , Mingyao Liu _{3,

5} , Qiong Xie ₁ , Yonghui Wang ₁ , Weiqiang Lu ₂

Affiliation

Aberrantly elevated adenosine in the tumor microenvironment exerts its immunosuppressive functions through adenosine receptors A_2AR and A_2BR. Antagonism of A_2AR and A_2BR 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_2AR/A_2BR activity and selectivity of novel 2-aminopyrimidine compounds. Substituting indole at the 4-/5-position produced potent A_2AR/A_2BR dual antagonism, whereas the 6-position of indole substitution gave highly selective A_2BR 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_2AR. Of note, dual A_2AR/A_2BR 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_2AR/A_2BR or A_2BR antagonists by fine-tuning structural modification.

中文翻译：

跨越 A2AR/A2BR 双重拮抗和 A2BR 拮抗之间边界的细微结构变化：一类基于 2-氨基嘧啶的新型衍生物

肿瘤微环境中异常升高的腺苷通过腺苷受体 A_2AR 和 A_2BR 发挥其免疫抑制功能。A_2AR 和 A_2BR 的拮抗作用有可能抑制肿瘤生长。在此，我们报告了第 4、5、6 或 7 位吲哚修饰对新型 2-氨基嘧啶化合物的 A_2AR/A_2BR 活性和选择性影响的系统评估。在 4-/5 位取代吲哚产生有效的 A_2AR/A_2BR 双重拮抗作用，而吲哚取代的 6 位产生高度选择性的 A_2BR 拮抗作用。分子动力学模拟表明，由于在 A_2AR 中与 E169 或 F168 发生水桥氢键相互作用，5-氰基化合物 7ai 的结合自由能低于 6-氰基化合物 7aj。值得注意的是，化合物 7ai 的双重 A_2AR/A_2BR 拮抗作用可以深度促进 T 细胞的活化和细胞毒功能。这项工作提供了一种通过微调结构修饰获得新型双重 A_2AR/A_2BR 或 A_2BR 拮抗剂的策略。

更新日期：2024-03-14

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