Synthesis and biological evaluation of novel benzamide derivatives as potent smoothened antagonists |
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| Affiliation: | 1. State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China;2. Department of Pharmaceutical and Biological Engineering, College of Chemical Engineering, Sichuan University, Chengdu 610065, China;1. Egyptian Petroleum Research Institute, P.O. Box 9540, Nasr City, Cairo 11727, Egypt;2. Department of Chemistry, Faculty of Science, Suez University, Suez, Egypt;1. Laboratório de Farmacognosia, Universidade de Brasília, Campus Universitário Darcy Ribeiro, Asa Norte, 70910-900 Brasília, DF, Brazil;2. Laboratório de Anatomia Vegetal, Universidade de Brasília, Brasília, Brazil;3. Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, Brazil;4. Laboratoire de Pharmacognosie, U.M.R./C.N.R.S. 8638, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, 4 Avenue de l’Observatoire, 75006 Paris, France;1. Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, United States;2. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States;3. The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States;1. Systems Immunity Research Institute, and Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK;2. Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA;3. ThermoFisher Scientific, Stafford House, Boundary Way, Hemel Hempstead HP2 7GE, United Kingdom;4. Vanderbilt Institute of Chemical Biology, Centre in Molecular Toxicology, Vanderbilt-Ingram Cancer Centre, Nashville, TN, USA |
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| Abstract: | A series of novel benzamide derivatives were prepared and evaluated using cell-based measurements. Among these compounds, 10f significantly inhibited Hedgehog signaling and showed equivalent or more potency than GDC-0449 in different tests. Furthermore, compound 10f potently inhibited the proliferation of Daoy, a medulloblastoma cell line that is reported to be resistant to GDC-0449, which indicated a promising prospect in the treatment of Hedgehog signaling pathway related cancer in clinical trial. |
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| Keywords: | Amide derivatives Hedgehog Smoothened antagonist |
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