Depsi-peptides

Rationalization of the results obtained in the substitution reactions prompted their application to topics of current interest, such as studies on the structures and biological activities of peptides, depsi-peptides, pseudo-peptides, or C2-symmetric... 

N-protected aminoacids 14 behave as carboxyl partners in Ag20 promoted reactions of 2-bromo-isobutyramides or -propanamides affording, respectively, esters of 2-hydroxy-isobutyramides (ref. 20a) or lactamides 15 (ref. 20b). While we plan further research on stereochemical and other aspects of these reactions, model units obtained from 2-bromo-isobutyramides have been used in conformational studies of depsi-peptides (ref. 21). 

Similarly, iterative NRPSs operate in a linear fashion but utilize at least one domain or module multiple times for the synthesis of a single NRP product. Thus, peptides assembled by iterative synthetases contain short, repeating units of peptide building blocks. In such systems, the terminal PCP-TE (or infrequendy PCP-C) didomain is responsible for both condensation of the repeating peptide units and chain release from the assembly line. NRPs biosynthesized in this manner include enniatin, enterobactin, bacillibactin, " gramicidin and the depsi-peptides valinomycin and cereulide. Of these examples, condensation of the precursor peptides for both enterobactin and gramicidin S has been extensively studied and will be discussed in detail. 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

Naturally / -amino acids that are not intermediates of the primary metabolism, e.g. /7-Ala 1, (R)-, or (S)-/7-AiB 2, which have been discussed previously, are less widespread in nature. Whereas a variety of natural /7-amino acids has been found as substructures of secondary metabolites, for example alkaloids, peptides, or depsi-peptides, their free counterparts, the free /7-amino acids, seem to be less common (see concluding remarks). 

Lydiamycins, cyclodepsipeptides ( depsi-peptides) isolated from the fermentation broth of Streptomyces lydicus (strain HKI0343). Lydiamycins A-C contain Ala, Leu, Ser, piperazic acid building block 1 (PBBl), dehydropiperazic acid building block 2 (PBB2), and 2-pentylsuccinic... 

In order to clarify the mechanism of the biosynthesis, enzyme-bound intermediates were investigated. It has been found, that the depsi-peptide hydroxyisovaleryl-N-methylvaline is an obligatory intermediate in the biosynthetic process. Three of these depsipeptides are then condensed to form the cyclohexadepsipeptide enniatin B. So far the following reaction sequence has been established ... 

Substances of the amphotericin D (a polyene), polyether (for example crown cyclic ethers), Antamanide (a peptide), and valinomycin (a depsi-peptide) represent structural types capable of complexing with alkali metal ions and thereby promoting their dissolution in fairly nonpolar solvents. Such compounds are known as ion carriers and some display antibiotic properties which may in part reside with activity in natural membranes. In order to evaluate structural changes upon such interesting functions, Gisin and Merri-field have synthesized a cyclododecapeptide (Chart 15) where the D-a-hy-droxyisovaleric acid and L-lactic acid units of valinomycin were replaced respectively with D-Pro and L-Pro. In MeCl-Aq the valinomycin analog was found to exhibit a seven times greater affinity for potassium picrate (to form a 1 1 hydrophobic complex) than that of the parent depsipeptide. 

Chen, Y. et al., Soluhon-phase parallel synthesis of a pharmacophore hhrary of HUN-7293 analogs a general chemical mutagenesis approach to defining structure-funchon properhes of naturally occm-ring cyclic (depsi)peptides, J. Am. Chem. Soc., 124, 5431, 2002. 

A simple method to determine the relative stereochemistry of statine amino acids (y-amino-jS-hydroxyacids) by using H NMR spectroscopy has been described by Preciado and Williams. They have shown that it is possible to assign the configuration of statine units within complex natural products by using a combination of chemical shift and coupling information derived from the a-methylene ABX system. The authors provided 73 examples whose complexity ranges from simple statine units to cyclic depsi-peptides, such as tamandarin B. 

Dehydrodidemnin B Phase II Trididemnum solidum Anticancer Cyclic depsi peptide... 

Scheme 4.4 Synthesis of the p-hydro5 -y,6-unsaturated acid present in the depsi-peptide natural products.

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