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Published on: August 10, 2017
Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors
Luisa M Bachmann1, Maria Hanl2, Felix Feller2
1Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.
Abstract:
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.
Insights
Novel dual inhibitors targeting histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) were synthesized and evaluated. While compounds C3 and C4 showed promising anticancer effects, simultaneous inhibition did not yield additive or synergistic results.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Biology
Background:
- Histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are frequently overexpressed in various cancers.
- Multi-target drugs (MTDs) offer an alternative to combination therapies for cancer treatment.
Purpose of the Study:
- To design, synthesize, and evaluate novel dual inhibitors targeting both HDAC and COX-2.
- To assess the in vitro anticancer activities and mechanisms of these dual inhibitors.
Main Methods:
- Parallel synthesis approach utilizing preloaded solid-phase resins.
- In vitro biological assays to determine inhibitory activities against HDAC and COX isoforms.
- Whole-cell HDAC inhibition assays, immunoblot experiments, and antiproliferative assays.
Main Results:
- Several synthesized compounds exhibited significant inhibitory activity against HDAC and COX isoforms.
- Compounds C3 and C4 demonstrated potent antiproliferative effects and induced apoptosis in cancer cells.
- Simultaneous inhibition of HDAC and COX did not lead to additive or synergistic anticancer effects.
Conclusions:
- Dual HDAC-COX inhibitors represent a viable therapeutic strategy for cancers overexpressing these targets.
- Compounds C3 and C4 are promising lead candidates for further anticancer drug development.
- The lack of synergistic effects warrants further investigation into the complex interplay of HDAC and COX inhibition in cancer.
