Abstract
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 |
|---|---|
| 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 - 26 Nov 2014 |
Keywords
- 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