Biological and structural investigation of tetrahydro-β-carboline-based selective HDAC6 inhibitors with improved stability

Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) 4 ) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S) S )-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, 29b , which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b S- 29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.