Synthesis and discovery of HDAC inhibitors using fluorous tags

Reversible acetylation plays a key role in defining chromatin states and in regulating transcription from genomic DNA differentially across distinct tissues. Acetylated histones recruit protein complexes responsible for transcriptional activation. Histone deacetylases (HDACs) function in this process by catalyzing the hydrolysis of N-acetyl groups on lysine residues found in the N-terminal tails of histone proteins, terminating transcription. This process mediates cell differentiation, correlates with epigenetic inheritance, and is deregulated in human disease, among others.; The development of potent and selective HDAC inhibitors is an important challenge for modern chromatin research. Not only do these compounds have high clinical value, they can help elucidate the function of individual HDACs and illuminate mechanisms governing genomic transcription. The identification of novel inhibitors has relied heavily on biochemical enzyme activity assays, which complicates the evaluation of small-molecule libraries. To this end, non-covalent immobilization of a collection of fluorous-tagged compounds was evaluated for its effectiveness at identifying HDAC inhibitors. These fluorous-based small-molecule microarrays were validated as an excellent approach to profiling fluorous-tagged compound libraries. Fluorous tags are also versatile protecting groups that facilitate chemical synthesis, and studies toward the synthesis of a conformationally diverse fluorous-tagged HDAC inhibitor library are described. The ability of fluorous tags to facilitate both small-molecule synthesis and screening prove it to be an effective and integrated platform for HDAC inhibitor discovery.