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 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.