Document Detail


Discovery of 5-Benzyl-3-phenyl-4,5-dihydroisoxazoles and 5-Benzyl-3-phenyl-1,4,2-dioxazoles as Potent Firefly Luciferase Inhibitors.
MedLine Citation:
PMID:  23286196     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Pekka Kalevi Poutiainen; Jorma Palvimo; Ari Hinkkanen; Arto Valkonen; Reino Laatikainen; Juha Tapio Pulkkinen; Topi Väisänen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-4
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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