Brant Michael G, Goodwin-Tindall Jake, Stover Kurt R, Stafford Paul M, Wu Fan, Meek Autumn R, Schiavini Paolo, Wohnig Stephanie, Weaver Donald F
Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto M5T 2S8, Canada.
Department of Chemistry, University of Toronto, Toronto M55 3H6, Canada.
ACS Med Chem Lett. 2018 Jan 11;9(2):131-136. doi: 10.1021/acsmedchemlett.7b00488. eCollection 2018 Feb 8.
Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: 1-substituted 5-indoleimidazoles and 1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure-activity relationship studies.
抑制吲哚胺2,3-双加氧酶（IDO1）是一种有吸引力的免疫治疗方法，可用于治疗多种癌症。该酶的失调也与包括阿尔茨海默病和关节炎在内的其他疾病有关。在此，我们报告了两个相关系列分子的基于结构的设计：1-取代的5-吲哚咪唑和1-取代的5-苯基咪唑。后一个（且更具活性）系列是通过Van Leusen咪唑合成反应中亚胺中间体的意外重排得到的。计算和构效关系研究支持了这两个抑制剂系列的结合模式的证据。
