Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles
Research output: Contribution to journal › Journal article › Research › peer-review
Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 57 |
Issue number | 22 |
Pages (from-to) | 9644-9657 |
Number of pages | 14 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 2014 |
- Cell Line, Tumor, Chemistry, Pharmaceutical, Computer Simulation, Crystallography, X-Ray, Drug Design, Drug Evaluation, Preclinical, Histone Deacetylase Inhibitors, Humans, Inhibitory Concentration 50, Kinetics, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Peptides, Cyclic, Protein Binding, Protein Conformation
Research areas
ID: 138228597