Fu Pan-Pan, Wang Qun, Zhang Qing, Jin Yang, Liu Jin, Chen Kai-Xian, Guo Yue-Wei, Liu San-Hong, Li Xu-Wen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
J Med Chem. 2023 Apr 27;66(8):5427-5438. doi: 10.1021/acs.jmedchem.2c01702. Epub 2023 Apr 11.
The total synthesis of the marine natural product naamidine J and a rapid structure modification toward its derivatives were achieved on the basis of several rounds of structure-relationship analyses of their tumor immunological activities. These compounds were tested for programmed death-ligand 1 (PD-L1) protein expression in human colorectal adenocarcinoma RKO cells. Among them, compound was found to efficiently suppress constitutive PD-L1 expression in RKO cells with low toxicity and further exerted its antitumor effect in MC38 tumor-bearing C57BL/6 mice by reducing PD-L1 expression and enhancing tumor-infiltrating T-cell immunity. This research work may provide insight for the discovery of new marine natural product-derived tumor immunological drug leads.
基于对海洋天然产物那米定J的肿瘤免疫活性进行的几轮构效关系分析，实现了其全合成以及对其衍生物的快速结构修饰。对这些化合物在人结肠腺癌RKO细胞中进行程序性死亡配体1（PD-L1）蛋白表达测试。其中，发现化合物能有效抑制RKO细胞中组成型PD-L1表达，且毒性低，并通过降低PD-L1表达和增强肿瘤浸润性T细胞免疫，在荷MC38肿瘤的C57BL/6小鼠中进一步发挥其抗肿瘤作用。这项研究工作可能为发现新的海洋天然产物衍生的肿瘤免疫药物先导物提供思路。
