The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here we report the preparation and systematic variation of phenothiazines and analogues containing a benzhydroxamic acid moiety as zinc-binding group. We evaluated their ability to inhibit selectively HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by Western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling *
A convenient method for N-arylethylation of aromatic amines and heterocycles under mild reductive conditions was developed using (2-methoxyvinyl)(hetero)arenes as building blocks and triethylsilane/trifluoroacetic acid as reducing agent. This protocol is compatible with numerous functional groups, and aliphatic amines are inert due to protonation.
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