基于苯并咪唑骨架的强效吲哚胺2,3-双加氧酶1（IDO1）抑制剂的鉴定
Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.
作者信息
Brant Michael G, Goodwin-Tindall Jake, Stover Kurt R, Stafford Paul M, Wu Fan, Meek Autumn R, Schiavini Paolo, Wohnig Stephanie, Weaver Donald F
机构信息
Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto M5T 2S8, Canada.
Department of Chemistry, University of Toronto, Toronto M55 3H6, Canada.
出版信息
ACS Med Chem Lett. 2018 Jan 11;9(2):131-136. doi: 10.1021/acsmedchemlett.7b00488. eCollection 2018 Feb 8.
Abstract
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.
摘要
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。
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