Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors

Institution:	1. Servicio de Medicina Interna, Hospital General Universitario de Ciudad Real, Ciudad Real, España;2. Servicio de Nefrología, Hospital General Universitario de Ciudad Real, Ciudad Real, España;1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;2. Department of Drug Metabolism and Pharmacokinetics, BioFocus, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK;3. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;4. Department of Biochemical and Cellular Pharmacology, BioFocus, Chesterford Research Park, Saffron Walden, Essex CB10 1XL, UK;5. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;6. LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK;7. Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;1. School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China;2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China;3. Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China;4. Shenzhen Institute, Guangdong Ocean University, Shenzhen 518116, China;5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China

Abstract:	PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed.

Keywords:	3-Phosphoinositide-dependent kinase 1 (PDK1) Inhibitor Buchwald–Hartwig cross-coupling Cross-coupling
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