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J Med Chem. 2014 Nov 26;57(22):9644-57. doi: 10.1021/jm501399d. Epub 2014 Nov 7.

Methyl effect in azumamides provides insight into histone deacetylase inhibition by macrocycles.

Author information

1
Department of Chemistry, Technical University of Denmark , Kemitorvet 207, DK-2800 Kongens Lyngby, Denmark.

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.

PMID:
25380299
DOI:
10.1021/jm501399d
[Indexed for MEDLINE]

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