Molecular insights into azumamide e histone deacetylases inhibitory activity.
Azumamide E, a cyclotetrapeptide isolated from the sponge Mycale izuensis, is the most powerful carboxylic acid containing natural histone deacetylase (HDAC) inhibitor known to date. In this paper, we describe design and synthesis of two stereochemical variants of the natural product. These compounds have allowed us to clarify the influence of side chain topology on the HDAC-inhibitory activity. The present contribution also reveals the identity of the recognition pattern between azumamides and the histone deacetylase-like protein (HDLP) model receptor and reports the azumamide E unprecedented isoform selectivity on histone deacetylases class subtypes. From the present studies, a plausible model for the interaction of azumamides with the receptor binding pocket is derived, providing a framework for the rational design of new cyclotetrapeptide-based HDAC inhibitors as antitumor agents.
Maulucci
Nakia
N
Department of Chemistry, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.
Chini
Maria Giovanna
MG
Micco
Simone Di
SD
Izzo
Irene
I
Cafaro
Emiddio
E
Russo
Adele
A
Gallinari
Paola
P
Paolini
Chantal
C
Nardi
Maria Chiara
MC
Casapullo
Agostino
A
Riccio
Raffaele
R
Bifulco
Giuseppe
G
Riccardis
Francesco De
FD
D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011161:Porifera; D011485:Protein Binding; D020033:Protein Isoforms
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D020033:Protein Isoforms; C516229:azumanide E