Synthesis and bioactivity of novel histone acetylation inhibitors: potential new drugs for treatment of cancer and inflammation

There is an increasing interest in histone acetyltransferases (HATs) as new therapeutic targets for treatment of diseases like, for example, inflammation and cancer. However, only few small and cell-permeable molecule inhibitors of HATs are currently available. The work described in this thesis focuses on the synthesis and biological evaluation of novel HAT inhibitors. The major challenge is to find potent and selective HAT inhibitors that show biological activity in cells. In the first part of this thesis we report the design and synthesis of potent isothiazolone-based inhibitors of the recombinant HAT PCAF, which are also cytotoxic for different cancer cell lines. Moreover, we elucidate the chemical reactivity of isothiazolones derivatives showing that isothiazolones might find applications in activity-based protein profiling studies. The second part of this thesis describes the development of novel HAT inhibitors using the natural product anacardic acid (AA) as starting point. Using a combination of molecular design, organic synthesis and enzyme inhibition studies, we develop several novel compounds that are selective inhibitors of the recombinant HAT Tip60 in comparison with the HATs PCAF and p300. Furthermore, we identify a new AA derivative that shows a twofold improved potency for inhibition of histone H4 acetylation in cell-based studies. In conclusion, the work described in this thesis provides new chemical tools for pharmacological studies to validate HATs inhibitors as potential new drugs for treatment of cancer and inflammation.