| Autor: |
Poutiainen PK; School of Pharmacy, University of Eastern Finland , P.O. Box 1627, FI-70211 Kuopio, Finland., Palvimo JJ, Hinkkanen AE, Valkonen A, Väisänen TK, Laatikainen R, Pulkkinen JT |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2013 Feb 14; Vol. 56 (3), pp. 1064-73. Date of Electronic Publication: 2013 Jan 17. |
| DOI: |
10.1021/jm301516q |
| Abstrakt: |
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 noncompetitive for both natural enzyme substrates (d-luciferin and ATP) and 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 (IC(50) = 59 nM), with five compounds having distinctly subnanomolar IC(50) values. The most efficient compounds inhibited the luminescence at concentrations lower than (1)/(100) in comparison to resveratrol (lowest IC(50) = 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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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