State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
Eur J Med Chem. 2017 Nov 10;140:293-304. doi: 10.1016/j.ejmech.2017.09.025. Epub 2017 Sep 18.
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, derivative 11r was the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds 11p and 11r bound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN-γ production, 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.
色氨酸 2,3-双加氧酶 1（IDO1）是癌症免疫治疗的一个有吸引力的靶点。本文中，我们合成了一系列新型咪唑异吲哚衍生物，并评价了它们抑制 IDO1 的能力。在这些化合物中，衍生物 11r 在基于 Hela 细胞的测定中具有纳摩尔效力的最活性化合物，而显示出可忽略的细胞毒性。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，它们可以显著促进 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，进行诱导契合对接（IFD）和量子力学/分子力学（QM/MM）计算，以了解这些化合物与 IDO1 蛋白的相互作用，这为进一步的结构修饰和优化提供了全面的指导。
