Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases |
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| Institution: | 1. Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany;2. Präklinische Targetentwicklung, Deutsches Krebsforschungszentrum, Heidelberg, Germany;3. Zoological Institute, Department of Structural Biology, Kiel University, Am Botanischen Garten 1-9, 24118 Kiel, Germany;1. Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia;2. Murdoch Childrens Research Institute, Melbourne, Victoria 3052, Australia;3. Royal Women''s Hospital, Melbourne, Victoria 3052, Australia;4. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3168, Australia;5. Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, Victoria 3004, Australia;1. Département de Chimie and PROTEO, Université Laval, 1045 Avenue de la Médecine, Québec G1V 0A6, Canada;2. Groupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, 2420 Rue de la Terrasse, Québec G1V 0A6, Canada;1. Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore;2. Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, PR China;1. Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany;2. Federal University of Alagoas (UFAL), Campus Arapiraca, NCEx, 57309-005 Arapiraca, Alagoas, Brazil;1. Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, People''s Republic of China;2. Engineering Center of Catalysis and Synthesis for Chiral Molecules at Fudan University, People''s Republic of China |
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| Abstract: | We identified and characterized β-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. β-Aminoketones with certain structural features form α,β-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP. |
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| Keywords: | Enzyme inhibition Irreversible inhibitors Methionine aminopeptidase Beta-aminoketone Prodrug |
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