萘环类PD-1/PD-L1抑制剂的设计、合成及生物活性评价  

Design, Synthesis and Biological Evaluation of Naphthalene Ring PD-1/PD-L1 Inhibitors

作　　者：赵磊 余龙波 欧阳宜强 郭文洁[2] 徐强[2] 高健 赖宜生[1] 

机构地区：[1]中国药科大学,新药研究中心,天然药物活性组分与药效国家重点实验室,江苏省代谢性疾病药物重点实验室,江苏 南京 [2]南京大学,生命科学学院,医药生物技术国家重点实验室,江苏 南京

出　　处：《药物化学》2021年第2期94-103,共10页Hans Journal of Medicinal Chemistry

摘　　要：以BMS-1018为先导化合物,通过替换联苯片段为萘环以及生物电子等排原理,结合分子对接技术,设计并合成了两个系列共18个新型萘环类PD-1/PD-L1小分子抑制剂,结构经1H-NMR和ESI-MS谱确证。采用均相时间分辨荧光法评价目标化合物对PD-1/PD-L1结合的抑制活性。结果表明,所有目标化合物对PD-1/PD-L1均显示不同程度的抑制活性。其中6个化合物A-8、A-9和B-5、B-6、B-8、B-9的活性较为突出,值得进一步研究。Using BMS-1018 as the lead compound, two series of novel naphthalene-based PD-1/PD-L1 small molecule inhibitors were designed and synthesized by replacing the biphenyl moiety with a naph-thalene ring and applying the principle of bioisosterism combined with molecular docking technol-ogy. The structures of the target compounds were confirmed by 1H-NMR and ESI-MS. The inhibitory activity of the compounds against the PD-1/PD-L1 interaction was evaluated by homogeneous time-resolved fluorescence. The results showed that all the target compounds displayed different degrees of inhibitory activity. Among them, six compounds A-8, A-9 and B-5, B-6, B-8, B-9 have out-standing activities, which are worthy of further study.

关 键 词：肿瘤免疫治疗 免疫检查点 PD-1/PD-L1抑制剂 生物活性 

分 类 号：R73[医药卫生—肿瘤]