Synthesis and In Vitro Biological Evaluation of <i>p</i>-Carborane-Based Di-<i>tert</i>-butylphenol Analogs
Sebastian Braun,
Sanja Jelača,
Markus Laube,
Sven George,
Bettina Hofmann,
Peter Lönnecke,
Dieter Steinhilber,
Jens Pietzsch,
Sanja Mijatović,
Danijela Maksimović-Ivanić,
Evamarie Hey-Hawkins
Affiliations
Sebastian Braun
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Sanja Jelača
Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bul. Despota Stefana 142, 11060 Belgrade, Serbia
Markus Laube
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany
Sven George
Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
Bettina Hofmann
Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
Peter Lönnecke
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Dieter Steinhilber
Institute of Pharmaceutical Chemistry, University of Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
Jens Pietzsch
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany
Sanja Mijatović
Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bul. Despota Stefana 142, 11060 Belgrade, Serbia
Danijela Maksimović-Ivanić
Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bul. Despota Stefana 142, 11060 Belgrade, Serbia
Evamarie Hey-Hawkins
Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.
