Discovery of 5-(pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
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| Affiliation: | 1. Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092 Shanghai, China;2. State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, 2005 Songhu Road, 200438 Shanghai, China;3. School of Pharmacy, Nantong University, 19 Qixiu Road, 226001 Nantong, China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;2. Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China;1. Center of Drug Screening and Evaluation, Wannan Medical College, Wuhu, Anhui 241000, PR China;2. Center for Reproductive Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, PR China;1. Université Paul Sabatier, UMR CNRS 5068, Laboratoire de Synthèse et Physicochimie de Molécules d’Intérêt Biologique, 118 Route de Narbonne, 31062 Toulouse Cédex 9, France;2. Ludwig Cancer Research Ltd (Brussels Branch) & de Duve Institute (Tumor Immunology & Antigen Processing Group), Avenue Hippocrate 74 (UCL B1.7403) B-1200, Bruxelles, Belgium;1. Department of Pharmaceutical Engineering, School of Food and Bioengineering, Xihua University, Chengdu 610039, China;2. Key Laboratory of Systematic Research, Development and Utilization of Chinese Medicine Resources, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu 610091, China;3. Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China;1. Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing, 100050, China;2. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing, 100050, China |
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| Abstract: | Early studies demonstrated that over expression of indoleamine 2,3-dioxygenase (IDO1) in tumor microenvironment results in tumor immune escape. Herein, in order to simplify the structure of two kinds of IDO1 inhibitors from marine alkaloid, Exiguamine A and Tsitsikammamines, we designed, synthesized a series of 1H-indole-4,7-dione derivatives and evaluated their inhibitory activity in IDO1 enzyme and in IFN-γ stimulated Hela cells in vitro. The structure-activity relationship demonstrated that 5-(pyridin-3-yl)-1H-indole-4,7-dione is a promising scaffold for IDO1 inhibitors and most compounds with this core showed moderate inhibition potency at micromole level. Our further enzyme kinetics experiments reveal that these new developed compounds might act as reversible competitive inhibitors of IDO1. |
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| Keywords: | Indoleamine 2,3-dioxygenase 1 Cancer immunotherapy Marine alkaloid Reversible competitive inhibitor |
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