Design,synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors |
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| Affiliation: | 1. Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;2. The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;1. Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, United States;2. Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden;1. Department of Chemistry, Temple University, Philadelphia, PA 19122, United States;2. Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States;1. Taras Shevchenko National University of Kyiv, Chemistry Department, 64/13 Volodymyrs''ka str., Kyiv, 01601, Ukraine;2. Laboratoire de Chimie Physique Macromoléculaire, ENSIC, Université de Lorraine, 1 rue Grandville, BP 451, 54001 Nancy, France |
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| Abstract: | Thirty novel triaryl compounds were designed and synthesized based on the known proteasome inhibitor PI-1840. Most of them showed significant inhibition against the β5c subunit of human 20S proteasome, and five of them exhibited IC50 values at the sub-micromolar level, which were comparable to or even more potent than PI-1840. The most active two (1c and 1d) showed IC50 values of 0.12 and 0.18 μM against the β5c subunit, respectively, while they displayed no obvious inhibition against the β2c, β1c and β5i subunits. Molecular docking provided informative clues for the subunit selectivity. The potent and subunit selective proteasome inhibitors identified herein represent new chemical templates for further molecular optimization. |
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| Keywords: | Non-covalent Proteasome inhibitors Triaryl compounds |
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