Dipeptide derivatives

Endotoxin and Muramyl Dipeptide Derivatives. Bacterial cell wall constituents such as the Hpopolysaccharide endotoxin and muramyl dipeptide, which stimulate host defense systems, show radioprotective activity in animals (204). Although endotoxin is most effective when given - 24 h before irradiation, it provides some protection when adrninistered shortiy before and even after radiation exposure. Endotoxin s radioprotective activity is probably related to its Hpid component, and some of its properties may result from PG and leukotriene induction (204). 

BicoZamycin. Bico2amycin (bicyclomycin) [38129-37-2] C22H2gN20y, shown in Figure 6, is a colorless, water-soluble diketopipera2ine or cycHc dipeptide derived from leucine and isoleucine. It was simultaneously isolated in 1972 in Japan from cultures of two different strains (166). 

Substitution of a dipeptide unit by a cychc dipeptide derivative within a peptide chain can induce certain conformational restraints that may alter the biological response via changing receptor selectivity. A facile procedure for synthesis of pyrazinone ring-containing opioid mimetics [21] has been elaborated, based on the cycHzation of readily available dipep-tidyl chloromethyl ketones [22] (Scheme 6). This method affords 2(IH)-pyrazinone derivatives containing substituents with desired functional groups at positions 3 and 6 in high yield. 

Muramyl dipeptide derivatives have also been microencapsulated in lactide/glycolide copolymers for use alone as an immuno potentiator. L-lactide/glycolide copolymers were used to deliver MDP-B30, a lipophilic compound, from very small microspheres (less than 5 pm in diameter). The amount of MDP-B30 required for tumor growth inhibitory activity of mouse peritoneal macrophages was 2000 times less for the controlled release MDP-B30 microspheres than for the unen-capsulated drug (134). 

Tabata, Y. and Ikada, Y., Activation of macrophage in vitro to acquire antitumor activity by a muramyl dipeptide derivative encapsulated in microspheres composed of lactide copolymer, J Control. Rel.. 6, 189, 1987. 

Initially, the cytotoxicity against chick embryo fibroblasts of BPA, tyrosine, tyrosine dipeptide, and the dipeptide derivatives used in the synthesis of the polymers shown in Fig. 7 were evaluated in a comparative experiment (43). The surface of standard tissue culture wells was coated with 5 mg of each test substance. Then the adhesion and proliferation of the fibroblasts was followed over a 7-day period. Among all test substances, BPA was clearly the most cytotoxic material. Monomeric tyrosine derivatives containing the ben-zyloxycarbonyl group were also cytotoxic, while tyrosine itself, tyrosine dipeptide, and most of the protected dipeptide derivatives did not noticeably interfere with cell growth and adhesion and were therefore classified on a preliminary basis as possibly "nontoxic."... 

After 7 days, the acute inflammatory response at the implantation site was evaluated. Bisphenol A resulted in a moderate level of irritation at the implantation site and was clearly the least biocompatible test substance. Tyrosine derivatives containing the benzyloxycar-bonyl group caused a slight inflammatory response, while all other tyrosine derivatives produced no abnormal tissue response at all. These observations indicate that tyrosine dipeptide derivatives, even if fully protected, are more biocompatible than BPA, a synthetic diphenol. ... 

Vegners R, Shestakova I, Kalvinsh I et al (1995) Use of a gel-forming dipeptide derivative as a carrier for antigen presentation. J Pept Sci 1 371-378... 

Figure 3. A homologous series of three tyrosine dipeptide derivatives gave rise to three new polyiminocarbonates that differed only in the length of the alkyl chain attached to the carboxylic acid group of the dipeptide.

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Twenty one rhena-/3-ketoimine derivatives of 14 different amino acids and one dipeptide have also been synthesized (37,38). The amino acid derivatives are prepared according to Eq. (3) in which the primary amine is an amino acid ester. A dipeptide derivative is formed via normal peptide coupling reactions, as shown in Eq. (4). In this reaction sequence, the ethyl... 

As anticipated, 33 binds in the desired manner, capturing the thiol by the aldehyde group (Scheme 5). Unexpectedly, 33 binds with only a twofold improved affinity when compared to the parent dipeptide derivative containing the unmodified pTyr residue [137]. 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Nolte and coworkers reported on the formation of micelles with a helical superstructure from AB amphiphilic diblock copolymers prepared from an amine-end-capped polystyrene that was used as the initiator for the polymerization of various dipeptide-derived isocyanides (Fig. 16). 

G. M. Barratt, C. Morin, M. Appel, and I. Seyler, Intracellular delivery of a muramyl dipeptide derivative by poly(DL-lactide) nanocapsules, in In vitro and ex vivo test systems to rationalize drug design and delivery, Paris, 1993, pp. 265-268. 

Aspartame, N-a-L-aspartyl-L-phenylalanine methyl ester, trade names NutraSweet , and Aspartil , is a dipeptide derivative. Like dipeptides aspartame is metabolised into the constituents, i.e. amino acids and methanol. Therefore studies into the metabolic behaviour and the fate of metabolites were carried out. Levels of blood aspartate and glutamate were measured after intake of high aspartame doses. Changes were transient and allegations of influences of high aspartame levels on brain function could never be verified. 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

After some optimization of the cycle time (time between replenishment of 60), effective amplification of the best binding peptide could be achieved. After seven cycles (112 hours), a 100-fold selectivity for the dipeptide derived from 60a and 60d could be observed over the next best binder, a remarkable result given that the ratio of binding constants is only 2.3 1. This selectivity is far higher than that typically observed in DCLs, and is based in part on the iterative nature of the experiment, an approach first demonstrated with success by Eliseev in abiotic dynamic systems [40,41]. 

Suetsuna K. (1998) Isolation and characterization of angiotensin I-converting enzyme inhibitor dipeptides derived from Allium sativum L (garlic). J Nutr Biochem 9 415—419. 

Perhaps the most useful and most widely employed multicomponent reaction in this context is the Ugi four-component reaction (U4CR and variations, Fig. 11), where an isonitrile, an aldehyde, an amine, and a carboxylic acid react to form a single product [65, 66]. The principal product is a dipeptide or dipeptide derivative and a high degree of diversity can be introduced by substituents (each of the four components can be varied), subsequent reactions, or by other reaction paths, which can lead to a vast varia-... 

Recently, it was reported that some dipeptide derivatives containing a histidine residue such as cyclo[(5)-His-(5)-Phe] (CHP) catalyze the alcoholysis of... 

The dipeptide derivative Z-D-Asp(OtBu)-L-Asp(OtBu)-OMe (6.0g, 11.69mmol) was hydrogenated in MeOH (500 mL) over Pd catalyst. After 7 h, the catalyst was filtered off and the soln was refluxed for 3 d. The solvent was removed under reduced pressure and the residue recrystallized (MeOH) yield 3.2 g (80%). 

In order to prove the importance of the rigid structure, as in the pipera-zinediones, these authors have carried out similar hydrogenation under identical conditions with the corresponding linear dipeptide derivatives. The ratio of the two diastereomers in the product was 49 51 (77JA8346)... 

Ingelheim) DE19911039, 2000 for a review see Doods et al., 2001). This compound, a Tyr-Lys dipeptide derivative, is a pure antagonist with high affinity towards the human CGRPi receptor (Kj = 14.4 pM). 

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