基于PD-L1肿瘤免疫苦豆碱类衍生物的合成与活性研究  

Synthesis and activity evaluation of aloperine derivatives based on PD-L1 tumor immunity

作　　者：张昕彤 王坤 曾庆轩 郭志浩 宋丹青[1] 李迎红[1] ZHANG Xin-tong;WANG Kun;ZENG Qing-xuan;GUO Zhi-hao;SONG Dan-qing;LI Ying-hong(Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China)

机构地区：[1]中国医学科学院、北京协和医学院医药生物技术研究所,北京100050 [2]温州医科大学药学院,浙江温州325035

出　　处：《药学学报》2022年第4期1085-1094,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81974494);中国医学科学院医学与健康科技创新工程(2021-I2M-1-030)。

摘　　要：本研究设计合成了28个全新12N取代苦豆碱衍生物并测定其在乳腺癌细胞MDA-MB-231中下调PD-L1水平的活性。其中,化合物7f具有较高的下调PD-L1活性,呈时间和剂量依赖性,且显示出较低的细胞毒性。7f可浓度依赖性地激活共培养T细胞对肿瘤细胞的杀伤活性,显示出肿瘤免疫治疗的潜力。进一步研究显示, 7f可能通过溶酶体途径介导PD-L1的降解。该研究为苦豆碱类化合物发展为一类全新小分子肿瘤免疫抑制剂提供了有益的指导。Totally 28 new 12N-substituted aloperine derivatives were designed, synthesized and evaluated for their down-regulating PD-L1 activities in breast cancer MDA-MB-231 cells. Among them, compound 7f could significantly down-regulate PD-L1 level in concentration-and time-dependent manners, and exhibit a low cytotoxicity. It activated the killing activity of co-cultured T cells against tumor cells in a concentration-dependent manner, showing the potential of tumor immunotherapy. Further study indicated that 7f mediated the degradation of PD-L1 through a lysosomal pathway. This study provides useful guidance for the development of aloperine compounds into new small molecule tumor immune suppressants.

关 键 词：苦豆碱类衍生物 PD-L1 抗肿瘤 肿瘤免疫抑制 溶酶体 

分 类 号：R914[医药卫生—药物化学]