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Novel Valdecoxib Derivatives by Ruthenium(II)-Promoted 1,3-Dipolar Cycloaddition of Nitrile Oxides with Alkynes - Synthesis and COX-2 Inhibition Activity.

Abstract

Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step via 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru(II)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured. The new the 3,4-diaryl-substituted isoxazoles possessing a small substituent (H and Me) displayed high COX-2 inhibition affinity (IC50=0.042–0.073 µM) and excellent selectivity (COX-2 SI > 2000). In contrast, the 3,5-diaryl substituted compounds displayed almost no COX activity. The introduction of a 4-fluorophenyl substituent resulted in retained high COX-2 affinity, making these compounds together with the feasible one step reaction promising candidates for the development of fluorine-18 labelled radiotracers.

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Publication details

The article was received on 14 Nov 2017, accepted on 12 Feb 2018 and first published on 13 Feb 2018


Article type: Research Article
DOI: 10.1039/C7MD00575J
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Novel Valdecoxib Derivatives by Ruthenium(II)-Promoted 1,3-Dipolar Cycloaddition of Nitrile Oxides with Alkynes - Synthesis and COX-2 Inhibition Activity.

    S. Roscales, N. Bechmann, D. H. Weiss, M. Köckerling, J. Pietzsch and T. Kniess, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C7MD00575J

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