Abstract：
Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA2AAR antagonist 2a, we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hA3AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA2AAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA2AAR (Ki,hA2A = 5.0 ± 0.5 nM, Ki,hA3/Ki,hA2A = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of 4a. These findings establish 4a as a viable immune-oncology therapeutic candidate.
摘要：
在前面的结构分析和8-芳基-2-己炔基核苷hA2AAR拮抗剂2a的构效关系（SAR）的基础上，我们策略性地反转C2/C8取代基并消除核糖部分。这些修饰旨在减轻核糖和腺苷受体之间的潜在空间相互作用。SAR研究结果表明，这种反转显著调节hA3AR结合亲和力取决于核糖的类型，而核糖的去除改变了通过hA2AAR的功能功效。在合成的衍生物中，2-芳基-8-己炔基腺嘌呤4a对hA2AAR的选择性最高（Ki，hA2A=5.0±0.5nM,Ki,hA3/Ki,hA2A=86）并有效阻断cAMP的产生并恢复PBMC中的IL-2分泌。在口服施用4a时观察到有利的药代动力学性质和抗癌作用与mAb免疫检查点阻断的显著增强。这些发现将4a确立为可行的免疫肿瘤学治疗候选物。
