The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1-11

Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε‐N‐acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and in vitro biochemical profiling of a series of compounds, including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compound collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn2+‐dependent HDACs. Potent inhibition was observed with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non‐hydroxamate class I and class IIb HDAC inhibitors. Zinc about it: We synthesized a series of compounds containing diverse zinc binding motifs and profiled their inhibitory activity against the 11 human histone deacetylases (HDAC1–11). From the results, we discovered silanediol to be a novel functionality with potential as a suitable design element in the preparation of new HDAC inhibitors. Compounds of this type show promise as future drug leads.