Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors


Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors

Bachmann, L. M.; Hanl, M.; Feller, F.; Sinatra, L.; Schöler, A.; Pietzsch, J.; Laube, M.; Hansen, F. K.

Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both his-tone 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 li-brary 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 demon-strated 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 western blot experiments. The most promising dual inhibitors C3 and C4 evoked antiprolifera-tive 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 treatment with vorinostat and celecoxib did not result in additive or synergistic anticancer activities.

Keywords: COX; HDAC; multi-target drugs; cancer; solid-phase synthesis

Permalink: https://www.hzdr.de/publications/Publ-36271
Publ.-Id: 36271