Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors
Luisa M. Bachmann,
Maria Hanl,
Felix Feller,
Laura Sinatra,
Andrea Schöler,
Jens Pietzsch,
Markus Laube,
Finn K. Hansen
Affiliations
Luisa M. Bachmann
Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany
Maria Hanl
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
Felix Feller
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
Laura Sinatra
Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany
Andrea Schöler
Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany
Jens Pietzsch
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany
Markus Laube
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328 Dresden, Germany
Finn K. Hansen
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.
