Azumamides A-E: Isolation, Synthesis, Biological Activity, and Structure-Activity Relationship

Abstract

Cyclic peptides are one of the important chemical groups in the HDAC inhibitor family. Following the success of romidepsin in the clinic, naturally occurring cyclic peptides with a hydrophilic moiety have been intensively studied to test their function as HDAC inhibitors. Azumamides A-E, isolated from Mycale izuensis, are one of the powerful HDAC inhibitor classes. Structurally, azumamides A-E consist of three D-α-amino acids and unnatural β-amino acids such as 3-amino-2-methyl-5-nonenedioic acid-9-amide (Amnna) and 3-amino-2-methyl-5-nonenoic-1,9-diacid (Amnda). Moreover, azumamides have a retro-arrangement peptide backbone, unlike other naturally occurring cyclopeptide HDAC inhibitors, owing to the D-configuration of all residues. This review summarizes the currently available synthetic methods of azumamides A-E focusing on the synthesis of β-amino acids and macrocyclization. In addition, we overview the structure-activity relationship of azumamides A-E based on reported analogs. Collectively, this review highlights the potentiality of azumamides A-E as an HDAC inhibitor and provides further developmental insight into naturally occurring cyclic peptides in HDAC inhibition.

Keywords: HDAC inhibitor; asymmetric synthesis; azumamide; macrocyclization; naturally occurring cyclic peptide; β-amino acid.

Figure 1

Examples of naturally occurring cyclic peptides characterized as HDAC inhibitors. Direction of N- to C-termini is indicated by arrow. The zinc-binding group is indicated by blue color.

Scheme 1

Synthetic approach of β-amino acid developed by Izzo and De Riccardis et al.

Scheme 2

Synthetic approach of β-amino acid developed by Ganesan et al.

Scheme 3

Synthetic approach of β-amino acid developed by Chandrasekhar et al.

Scheme 4

Synthetic approach of β-amino acid developed by Olsen et al.

Figure 2

Macrocyclization of azumamides A-E.

Figure 3

Binding modes of largazole (green) and SAHA (yellow) obtained from the co-crystal structure of HDAC8 complexed with largazole (PDB: 4RN0) or SAHA (PDB: 1T69); Zinc ion (Zn²⁺) presents as a red ball shape. This figure was generated using Pymol.