Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies
Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies
复制标题
发现咪唑异吲哚衍生物作为有效的 IDO1 抑制剂：设计、合成、生物学评价和计算研究
DOI：
10.1016/j.ejmech.2017.09.025
复制
发表时间：
2017
影响因子：
6.7
通讯作者：
Lai Yisheng
中科院分区：
文献类型：
--
作者：
Zou Yi;Wang Fang;Wang Yan;Sun Qirui;Hu Yue;Li Yuezhen;Liu Wen;Guo Wenjie;Huang Zhangjian;Zhang Yihua;Xu Qiang;Lai Yisheng
Indoleamine-2,3-dioxygenase-1 (IDO1) 是癌症免疫治疗的一个有吸引力的靶点。在此，制备了一系列新型咪唑异吲哚衍生物并评估了它们抑制 IDO1 的能力。其中，在基于 Hela 细胞的测定中，derivative11r 是最具活性的化合物，具有纳摩尔效力，同时显示出可忽略不计的细胞毒性。紫外-可见光谱研究表明化合物11p和11r与IDO1结合并与血红素铁配位。此外，它们还可以显着促进 T 细胞增殖，增加 IFN-γ 的产生，并减少 Foxp3+ 调节性 T 细胞的数量。最后，通过诱导拟合对接（IFD）和量子力学/分子力学（QM/MM）计算来了解这些化合物与IDO1蛋白的相互作用，为进一步的结构修饰和优化提供全面的指导。
Indoleamine-2,3-dioxygenase-1 (IDO1) is an attractive target for cancer immunotherapy. Herein, a series of novel imidazoleisoindole derivatives were prepared and evaluated for their ability to inhibit IDO1. Among these, derivative11rwas the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds11pand11rbound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN-γproduction, and reduce the numbers of Foxp3+regulatory T cells. Finally, induced fit docking (IFD) and quantum mechanics/molecular mechanics (QM/MM) calculation were performed to understand the interactions of these compounds to IDO1 protein, which provided a comprehensive guide for further structural modification and optimization.