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Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors
Institution:1. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea;2. Department of Physician Education and Training, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea;3. Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea;4. Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu, South Korea;1. Hunter College, City University of New York, Department of Chemistry, 695 Park Avenue, NY 10065, USA;2. The Graduate Center, City University of New York, 365 5th Avenue, New York, NY 10016, USA;3. LaGuardia Community College, Department of Chemistry, 31-10 Thompson Avenue, LIC, NY 11104, USA;1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613, United States;2. Division of the National Toxicology Program, NIEHS, RTP, NC 27709, United States;1. School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China;2. China Nuclear Power Design Co. Ltd., Building 5, Tian''an Cyber Park, Huangge Road, Shenzhen 518000, China;1. New York University Perlmutter Cancer Center, Department of Radiation Oncology, New York, NY;2. Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Chicago, IL;3. Instituto Nacional de Enfermedades Neoplásicas, Department of Radiation Oncology, Surquillo, Peru
Abstract:The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.
Keywords:Inhibitors of Apoptosis Proteins  XIAP  cIAP  Smac  Structure-based drug design  Ring-closing metathesis
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