Novel valdecoxib derivatives by ruthenium(<scp>ii</scp>)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes – synthesis and COX-2 inhibition activity

  1. Roscales García, Silvia 123
  2. Bechmann, Nicole 123
  3. Weiss, Daniel Holger
  4. Köckerling, Martin
  5. Pietzsch, Jens 123
  6. Kniess, Torsten 123
  1. 1 Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany
  2. 2 University of Rostock
    info

    University of Rostock

    Rostock, Alemania

    ROR https://ror.org/03zdwsf69

  3. 3 Department of Chemistry and Food Chemistry, Technische Universität Dresden, Bergstraße 66, 01062 Dresden, Germany
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Revista:
MedChemComm

ISSN: 2040-2503,  2040-2511

Año de publicación: 2018

Volumen: 9

Número: 3

Páginas: 534-544

Tipo: Artículo

DOI: 10.1039/C7MD00575J GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: MedChemComm

Resumen

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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