State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University , Handan Road 220, Shanghai 200433, China.
J Med Chem. 2013 Nov 14;56(21):8321-31. doi: 10.1021/jm401195n. Epub 2013 Oct 25.
Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO-1 inhibitor by screening of indole-based structures. Three series of 13 tryptanthrin derivatives were synthesized, and the structure-activity analysis was undertaken. The optimization led to the identification of 5c, which exhibited the inhibitory activity at a nanomolar level. In vitro 5c dramatically augmented the proliferation of T cells. When administered to Lewis lung cancer (LLC) tumor-bearing mice, 5c significantly inhibited IDO-1 activity and suppressed tumor growth. In addition, 5c reduced the numbers of Foxp3(+) regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses.
色氨酸 2,3-双加氧酶（IDO-1）作为一种新的治疗靶点，正在被广泛研究，以用于治疗癌症、神经紊乱和其他以病理性色氨酸代谢为特征的疾病。然而，目前已知的 IDO-1 抑制剂只有少数几种结构类型。在这项研究中，通过对吲哚类结构的筛选，发现天然化合物色胺酮是一种新型有效的 IDO-1 抑制剂。合成了 13 种色胺酮衍生物的三个系列，并进行了结构-活性分析。通过优化，鉴定出具有纳摩尔级抑制活性的 5c。体外实验表明，5c 能显著促进 T 细胞的增殖。当给予Lewis 肺癌（LLC）荷瘤小鼠时，5c 能显著抑制 IDO-1 活性并抑制肿瘤生长。此外，5c 减少了已知可防止有效抗肿瘤免疫反应发展的 Foxp3(+)调节性 T 细胞（Tregs）的数量。
