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.
Department of Chemistry, Technical University of Denmark , Kemitorvet 207, DK-2800 Kongens Lyngby, Denmark.
Alex R
AR
Maolanon
Jesper S
JS
Villadsen
Niels J
NJ
Christensen
Casper
C
Hoeck
Tina
T
Friis
Pernille
P
Harris
Charlotte H
CH
Gotfredsen
Peter
P
Fristrup
Christian A
CA
Olsen
D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation
D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D010456:Peptides, Cyclic; C534894:azumamide E