| Discovery of 5-Benzyl-3-phenyl-4,5-dihydroisoxazoles and 5-Benzyl-3-phenyl-1,4,2-dioxazoles as Potent Firefly Luciferase Inhibitors. | |
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MedLine Citation:
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PMID: 23286196 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Luciferase reporter assays are commonly used in high-throughput screening methods. Here, we report new firefly luciferase (FLuc) inhibitors based on 5-benzyl-3-phenyl-4,5-dihydroisoxazoles and 5-benzyl-3-phenyl-1,4,2-dioxazoles, which showed up as "false positives" in a luciferase reporter gene-based assay for nuclear receptor antagonists. The inhibition was shown to be non-competitive for both natural enzyme substrates (D-luciferin and ATP), selective to FLuc and proven to arise from a direct interaction between the enzyme and the inhibitor. Of the 63 evaluated compounds, 28 showed significantly better inhibition potency than the well-known inhibitor resveratrol (IC50 = 59 nM), with 5 compounds having distinctly sub-nanomolar IC50 values. The most efficient compounds inhibited the luminescence at concentrations lower than 1/100 in comparison to resveratrol (lowest IC50 = 0.26 nM) and can thus be considered to belong to the most potent FLuc inhibitors reported thus far. Overall, the novel inhibitors form a unique molecular library for structure-activity relationship (SAR) analyses. |
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Authors:
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Pekka Kalevi Poutiainen; Jorma Palvimo; Ari Hinkkanen; Arto Valkonen; Reino Laatikainen; Juha Tapio Pulkkinen; Topi Väisänen |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-4 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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