Crystal structure of histone deacetylase 6 complexed with (R)-lipoic acid, an essential cofactor in central carbon metabolism

Chemical Versatility in Catalysis and Inhibition of the Class IIb Histone Deacetylases

“…For example, the inhibitory potencies and binding modes of cyclic tetrapeptide and depsipeptide natural product inhibitors of HDACs recently inspired the de novo design of macrocyclic octapeptides and nonapeptides exhibiting nanomolar inhibitory potencies. , The zinc-binding group of these inhibitors is the thiol moiety of an unnatural amino acid that displaces the zinc-bound water molecule and coordinates to zinc as the thiolate anion. Similar zinc coordination modes have also been observed for the thiol groups of the marine natural product largazole, the reduced form of the cofactor ( R )-lipoic acid, and a mercaptoacetamide inhibitor. − Intriguingly, the structures of two different macrocyclic peptides complexed with HDAC6 reveal only water-mediated hydrogen bonds between the enzyme and the inhibitor in the outer active site cleft. , The same cushion of water molecules that accommodates the binding of these large inhibitors may similarly accommodate a wide variety of structurally diverse protein substrates.…”

Design, synthesis, and histone deacetylase inhibition study of novel 4‐(2‐aminoethyl) phenol derivatives

“…[5] HDACs are a class of enzymes that cause chromatin condensation and transcriptional repression by deacetylating the lysine residue of core histone and other cellular proteins. [6][7][8] HDACs are engaged in suppressing gene transcription through these epigenetic changes, which ultimately result in the silencing of tumor suppressor genes. Many cancer cell lines and tumor tissues have been found to display different HDACs abnormally.…”

“…1 H NMR (400 MHz, DMSO-d 6 ) δ anhydride(6, 193 mg, 1 mmol) was added. The mixture was stirred and heated under reflux at 110°C for 12 h. Then the warm reaction mixture was cooled to room temperature, and the product was precipitated by adding cool water, filtered out, and washed thoroughly with water.…”