Abstract
Faced with the need to find new drugs for all kinds of diseases, science sees that Nature offers numerous classes of compounds showing an impressively high biological potential. Among those are the cyclodepsipeptides, hybrid structures composed of amino and hydroxy acids. In the past decades numerous cyclodepsipeptides have been isolated and their potential as drugs has been studied extensively. For several cyclodepsipeptides total syntheses both in solution and on solid-phase have been established, allowing the production of combinatorial libraries. In addition, the biosynthesis of specific cyclodepsipeptides has been elucidated and used for the chemoenzymatic preparation of nonnatural analogues. This review summarizes the recent literature on cyclic tetra- to decadepsipeptides, composed exclusively of α-amino- and α-hydroxy acids.
Highlights
Cyclodepsipeptides constitute a large family of peptide-related natural products consisting of hydroxy and amino acids linked by amide and ester bonds
In the living cell cyclodepsipeptides are synthesized by giant multi-domain nonribosomal peptide synthetases (NRPs), following the so-called thiol template mechanism which features the domain organization C1-A1-T1-C2-A2-MT-T2a-T2b (Figure 1)
In 1989 the Waki group presented a total synthesis of AM-toxin II (2) and [L-Phe3]AM-toxin II (8), an analogue of 2, in which L-2-amino-5-phenylpentanoic acid was replaced for a L-Phe (Scheme 1) [22]
Summary
Cyclodepsipeptides constitute a large family of peptide-related natural products consisting of hydroxy and amino acids linked by amide and ester bonds. The cyclic nature and frequent N-methylation of amino acid residues confer resistance to hydrolyzing enzymes which results in enhanced oral bioavailability. Due to their unique structural and biological properties cyclodepsipeptides have emerged as promising lead structures for applications in crop protection (enniatins) as well as in human (aureobasidine) and veterinary medicine (PF1022). The use of large excesses of hydroxy acids in the coupling reaction is hampered by their high prices and limited availability compared to ribosomal amino acids. For other classes of depsipeptides the reader is referred to more specific literature [9,10,11,12]
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