Macrocycles cyclic depsipeptides

A host of carriers, with a wide variety of ion selectivities, have been proposed for this task. Most of them have been used for the recognition of alkali and alkaline metal cations (e.g., clinically relevant electrolytes). A classical example is the cyclic depsipeptide valinomycin (Fig. 5.13), used as the basis for the widely used ISE for potassium ion (38). This doughnut-shaped molecule has an electron-rich pocket in the center into which potassium ions are selectively extracted. For example, the electrode exhibits a selectivity for K+ over Na+ of approximately 30,000. The basis for the selectivity seems to be the fit between the size of the potassium ion (radius 1.33 A) and the volume of the internal cavity of the macrocyclic molecule. The hydrophobic sidechains of valinomycin stretch into the lipophilic part of the membrane. In addition to its excellent selectivity, such an electrode is well behaved and has a wide working pH range. Strongly acidic media can be employed because the electrode is 18,000 times more responsive to K+ than to H+. A Nernstian response to potassium ion activities, with a slope of 59mV/pK+, is commonly observed... 

Guidelines for the synthesis of cyclopeptides have it that pendant groups should be connected to the cyclic scaffold after ring closure. Moreover, peptide bond formation is generally preferred to ester bond formation as a means to accomplish macrocyclization of depsipeptide frameworks, and it is also well established that primary amino groups react more efficiently than secondary ones in peptide bond forming reactions i.e., secondary amides are more readily formed than tertiary ones. Retrosynthetic dissection of the only pair of secondary amide bonds in luzopeptin A-C precursor 11 leads to pentadepsipeptide 12 (Scheme 3). 

As already mentioned, the depsipeptides associate ester bonds with peptide bonds. As most of the depsipeptides of cyanobacteria are macrocyclic, this concerns lactone and lactam fimctions. Laingolide, laingolide A, madangolide and palmyrohde A are simple cyclic depsipeptides (one... 

Among the macrocyclic natural and synthetic drugs the cyclic peptides and cyclic depsipeptides play a central role in particular as anti-infective" and... 

Enantiomerically pure non-proteinogenic amino acids have attracted recent attention due to their antibiotic [1], antifungal [2], cytotoxic [3], and other important pharmacological properties [4]. Frequently, they also occur incorporated in natural products, such as peptides, depsipeptides, and other macrocyclic compounds. Other important applications are to serve as building blocks in asymmetric synthesis. A specifically prominent class of them are cyclic 3- and y-amino acids, the subject to which the present chapter is dedicated. 

To achieve selectivity in a classical metal-binding HDAC inhibitor, the cap needs to contain functionality for additional interactions with the rim . Of the inhibitors described above, the cyclic tetrapeptides have this potential due to their large macrocyclic scaffold, but have yet to result in clinical candidates. Structurally, the most complex HDAC inhibitors are the depsipeptide natural products exemplified by FK228. These compounds, which are treated separately in the next section, have even more elaborate caps , and are the best-documented example of selective HDAC inhibitors. 

Peptide antibiotics. Antibiotics with linear or cyclic oligopeptide structures containing not only L- amino acids but often also unusual, non-proteinogenic amino acids. Homopeptides are built up exclusively of amino acids (e.g., gramicidins), the so-called heteropeptides also contain other structural elements, e.g., hydroxamic acids. Macrocyclic Ra. containing one or more ester bonds in the ring are known as peptide lactones (e.g., hormaomycin) or depsipeptides (e.g., valinomycin). 

After the cyclic tetrapeptides, the bicyclic depsipeptides were the second class of macrocyclic natural product HDAC inhibitor to be discovered. The first and foremost example is FK228 (36, Figure 4.14), discovered by high-throughput screening at Fujisawa using a phenotypic assay for compounds with the ability to revert the morphology of ras-transformed cancer cells and... 

---