Methyl Effect in Azumamides Provides Insight Into Histone Deacetylase Inhibition by Macrocycles

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-11, Vol.57 (22), p.9644-9657
Main Authors: Maolanon, Alex R, Villadsen, Jesper S, Christensen, Niels J, Hoeck, Casper, Friis, Tina, Harris, Pernille, Gotfredsen, Charlotte H, Fristrup, Peter, Olsen, Christian A
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Chemistry, Pharmaceutical - methods
Computer Simulation
Crystallography, X-Ray
Drug Design
Drug Evaluation, Preclinical
Histone Deacetylase Inhibitors - chemical synthesis
Histone Deacetylase Inhibitors - chemistry
Humans
Inhibitory Concentration 50
Kinetics
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
Peptides, Cyclic - chemistry
Protein Binding
Protein Conformation
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501399d