Cyclic dipeptide

A comparison of the structures of penicillin and Dalanyl-Dalanine (cf. structures 41 and 42) shows that there is a great deal of similarity between the two molecules. Penicillin is essentially an acylated cyclic dipeptide of Dcysteine and Dvaline (84). As such, it contains a peptide bond, that of the /3-lactam ring, that can acylate the enzyme. Labeling studies of the peptidoglycan transpeptidase of Bacillus subtilis indicate that radioactive penicillin reacts with a sulfhydryl group of a cysteine residue of the enzyme (86). 

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

Funasaki, N., Hada, S., and Neya, S., Conformational effects in reversed-phase liquid chromatographic separation of diastereomers of cyclic dipeptides, Anal. Chem., 65, 1861, 1993. 

The variety of prebiotic organic reactions seems to be almost unlimited. Strasdeit et al. (2002) from the University of Hohenheim (Germany) reported the synthesis of zinc and calcium complexes of the amino acids valine and isovaline. They assume that these could have had a certain significance on the mineral-rich primeval Earth on heating to 593 K under nitrogen, valine was converted to the corresponding cyclic dipeptide. 

A biomimetic method using a cyclic dipeptide (39) is available. In the presence of HCN in toluene containing 2mole% of (39), benzaldehyde is converted into the (/ )-cyanohydrin in 97% yield (97% cc)1 lfi. ... 

Biomimetic reactions should also be considered for the preparation of optically active cyanohydrins (using a cyclic dipeptide as catalyst) and also for the epoxidation of a, (3-unsaturated ketones (using polyleucine or congener as a catalyst). 

FIGURE 6.1 Constitutional factors affecting the reactivity of functional groups. (A) The reactivity of W depends on the location of the residue. (B) The amino group of a dipeptide ester reacts with the ester carbonyl to form a cyclic dipeptide amino groups of other peptide esters do not react in this manner. (C, D) Reactions between residues of identical configuration do not occur at the same rates as reactions between residues of opposite configuration. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

An important contribution was recently made by Inoue and co-workers (35) (eq. [4]). Using the chiral cyclic dipeptide cyclo(L-Phe-L-His) these authors obtained a better than 90% e.e. in the reaction of benzaldehyde with cyanide ion. The preparation of the enantiomeric unnatural dipeptide obviously poses far fewer problems than the synthesis of an enantiomeric enzyme. It appears that, at least in principle, optically pure cyanohydrins of the desired configuration are accessible via catalysis by chiral amines or amides. 

The cyclic dipeptides or diketopiperazines (DKPs) 6-10 are yet another class of small diffusible signal molecules that has been isolated from the culture supernatants of R aeruginosa, Pseudomonasputida WCS 358 and other Gramnegative bacteria. Their role in cross-talk with AHL-dependent QS has been demonstrated but their physiological function is not known [20,21]. 

Exogenous factors affecting the rate of cyclic dipeptide formation 680... 

Cyclic dipeptides are heterocyclic compounds comprising of two amino acid residues linked to a central diketopiperazine (DPK) ring structure. The general structure for DKPs can be seen in Figure... 

Cyclic dipeptides also known as cyclo dipeptides, DKPs, 2,5-dioxopiperazines (DOPs), or dipeptide anhydrides. 

Most cyclic dipeptides found to date appear to... 

Table 1 Some naturally occurring simple cyclic dipeptides in the protist and plant kingdoms Diketopiperazine (all amino acids are in the L-configuration) Species...

Cyclic dipeptides, bearing the DKP ring, in which the amide linkages are cis, are known to represent the simplest form of homodetic cyclic peptides. ... 

They are of interest in studies on the thermodynamic behavior of nonionic compounds in aqueous media because they have the ability of forming hydrogen bonds with the solvent (through the two r/j-amide groups in the cyclic dipeptide ring), and give rise to hydrophobic interactions. ... 

Conformationally restricted cyclic dipeptides have several advantages over their linear counterparts ... 

It appears that cyclic dipeptides are indeed an unexplored class of bioactive agents that may hold great promise for the future. ... 

Varying concentrations of the respective cyclic dipeptides were exposed to a range of temperatures and pH values over a 6- to 24-week period. 

Certain cyclic dipeptides have the ability to be transported by additional paracellular mechanisms, thereby enhancing their transport. " Not only absorptive transport but also excretive transport are observed for certain cyclic dipeptides. The intestinal absorption of certain cyclic dipeptides consists of carrier-mediated absorptive... 

The conformations and molecular structures of cyclic dipeptides containing the DKP ring have been studied by a... 

DKPs are simple and easy to obtain and are quite common by-products of synthetic, spontaneous, and biological formation pathways. DKP formation has been well documented as side reactions of solid-phase and solution-phase peptide synthesis. In addition, DKPs have been shown to be decomposition products of various peptides, proteins, and other commercial pharmaceuticals. Cyclic dipeptides were found to be present in solutions of human growth hormone, bradykinin, histerlin, and solutions of agents within the classes of penicillins and cephalosporins. " DKPs are also enzymatically synthesized in several protists and in members of the plant kingdom. Hydrolysates of proteins and polypeptides often contain these compounds and they are commonly isolated from yeasts, lichens, and fungi. ... 

Cyclo(Gly-Gly) was the first cyclic dipeptide synthesized and elucidated, since then a wide variety of members of the cyclic dipeptide family have been synthesized by various methodologies. The cyclic dipeptides were initially prepared by the action of ammonia on the free dipeptide esters, liberated from the corresponding amine salts. The long duration of exposure to ammonia, required by the free dipeptide esters to effect cyclization, lead to extensive racemization when employing optically pure linear dipeptide precursors. Early cyclic dipeptide synthetic methods have involved the following ... 

The rates of formation of various cyclic peptides and DKPs have been documented and shown to be affected by a wide range of physicochemical and structural parameters. Goolcharran and Borchardt examined the effects of exogenous (i.e., pH, temperature, buffer species, and concentration) and endogenous (i.e., primary sequences) factors affecting the rate of cyclic dipeptide formation, using the dipeptide analogues of X-Pro-/)-nitroaniline (X-Pro-/>NA where X represents the amino acid residue of the respective cyclic dipeptide). 

The intramolecular aminolysis reaction was also shown to be involved in the formation of (Gly-Gly) and the biosynthetic pathway of the biologically active cyclic dipeptide cyclo(His-Pro), found throughout the CNS, peripheral tissue, and body fluids. ... 

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