Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
Bioorg Med Chem. 2019 Apr 15;27(8):1605-1618. doi: 10.1016/j.bmc.2019.03.005. Epub 2019 Mar 5.
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in tumor immune escape and has emerged as a promising target for cancer immunotherapy. In this study, a novel series of 2,5-dimethylfuran-3-carboxylic acid derivatives were designed, synthesized and evaluated for inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among these, compound 19a exhibited excellent IDO1 inhibitory activity (HeLa cellular IC = 4.0 nM, THP-1 cellular IC = 4.6 nM). Further molecular docking studies revealed that the compound 19a formed a coordinate bond with the heme iron through the carboxylic acid moiety. These results indicate that compound 19a is a potential IDO1 inhibitor for further investigation.
吲哚胺 2,3-双加氧酶 1（IDO1）在肿瘤免疫逃逸中发挥着重要作用，已成为癌症免疫治疗的一个有前途的靶点。在这项研究中，设计、合成了一系列新型的 2,5-二甲基呋喃-3-羧酸衍生物，并对其抑制 IDO1 的活性进行了评价，探讨了它们的构效关系。其中，化合物 19a 表现出优异的 IDO1 抑制活性（HeLa 细胞 IC=4.0nM，THP-1 细胞 IC=4.6nM）。进一步的分子对接研究表明，该化合物通过羧酸部分与亚铁血红素形成配位键。这些结果表明，化合物 19a 是一种潜在的 IDO1 抑制剂，值得进一步研究。
