Dipeptide aspartyl

Alitame. A new group of aspartyl-dipeptide sweeteners became known to the pubHc in 1983 (95). Alitame [80863-62-3] L-aspartyl-D-alanine... 

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. 

FIGURE 6.15 Imide formation from a dipeptide sequence containing an aspartyl residue with side-chain functional group in various states followed by generation of two peptide chains resulting from cleavage at the bonds indicated by the dashed arrows. The reaction is catalyzed by base52 or acid. [Merrifield, 1967]. The table shows the effect of the nature of the substituent on the extent of this side reaction. Dmpn = 2,4-dimethylpent-3-yl. 

During work on a series of aspartyl dipeptides containing ACC 71 (vide supra, Eq. (28), Sect. 4) at the carboxyl terminus, it was reported that dispartame Asp-ACC-OMe had a distinct sweet taste [302] and that the corresponding n-propyl ester had 250-300 times the sweetness of sucrose [303]. However, replacement of phenylalanine by 2,3-methanophenylalanine gave tasteless analogues of aspartame [293, 304], and some dimethyl-ACC 214 (methanovaline) and tri-methyl-ACC 215 aspartame analogues [Asp-(Me)n-ACC-OMe] have a bitter taste. These taste properties, which depend on the number and position of the methyl substituents, have been explained on the basis of topochemical models thus, a L-shaped conformation of the dipeptide is necessary for sweet taste, Eq. (86) [3051. 

We synthesized the ketomethylene, , and hydroxyethylene,8, isosteres of a Leu-Ala dipeptide sequence in order to explore the importance of the two extra atoms in statine relative either to substrate or to the tetrahedral intermediate (Figure 1) in another aspartyl protease system. The compounds were synthesized by the routes outlined in Scheme I. This route was chosen so as to provide steric control at C-2 and C-5 of both 7 and 8 as well as to provide ready access to C-4 labeled analogs. Details of the synthesis have been described else-where.(23.24) Inhibitors were synthesized in which Leu-Ala dipeptide Isosteres replaced either Sta or Sta-Ala in known pepstatin analogs. Inhibition of porcine pepsin was determined using the reported spectrophotometric assay (Table I).(25)... 

Case Study Applications L-Aspartyl Dipeptide Sweeteners... 

Iwamura(51) has investigated the structure-sweetness relationship in four classes of L-aspartyl dipeptides using linear free energy descriptors and multi-dimensional regression analysis. In essence, the Hansch methodology was employed. The four classes of compounds are - ... 

The analysis, in composite over the four classes of L-aspartyl dipeptides suggests that the electron-withdrawing effect of substituents directed to the peptide bond, and the steric dimensions of the molecules, are important in eliciting the sweet taste. The values of the regression coefficients of the a term in the QSAR equations for L-aspartic acid amides, L-aspartylaminoethylesters, and L-aspartylaminopropionates all... 

Aspartame. Aspartame [22839-47-0] [53906-69-1] (APM, L-aspartyl-L-phenylalanine methyl ester) (1), also known under the trade names of NutraSweet and EQUAL, is the most widely used nonnutritive sweetener worldwide. This dipeptide ester was synthesized as an intermediate for an antiulcer peptide at G. D. Searle in 1965. Although this compound was known in the literature, its sweet taste was serendipitously discovered when a chemist licked his finger which was contaminated with it. Many analogues, especially the more stable esters, were made (6) and their taste qualities and potencies determined. It was the first compound to be chosen for commercial development. Following the purchase of G. D. Searle by Monsanto, the aspartame business was split off to become a separate Monsanto subsidiary called the NutraSweet Company. 

Alitame. A new group of aspartyl-dipeptide sweeteners became known to the public in 1983 (95). Alitame [80863-62-3 ], l- as p a rtyl- d - alanine A -(2,2,4,4-tetramethylthietan-3-yl)armde (16), was selected for commercial development. In 1986 Pfizer filed a food additive petition with the FDA. As of December, 1996, it was still pending. Alitame was approved for use as a sweetener by Australia in 1993, by China, Mexico, and New Zealand in 1994, by Indonesia in 1995, and by Colombia in 1996. 

L-aspartyl-L-phenylalanine methyl ester) was used instead for the evaluation of a dipeptide. 

No generalizations can be made about the molecular weights of biologically active peptides and proteins in relation to their functions. Naturally occurring peptides range in length from two to many thousands of amino acid residues. Even the smallest peptides can have biologically important effects. Consider the commercially synthesized dipeptide L-aspartyl-L-phenylalanine methyl ester, the artificial sweetener better known as aspartame or NutraSweet. 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Other peptides, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), have a sweet taste. Several studies have been carried out to relate the structure and taste of analogs of this dipeptide (25). Tsang et al. (26) reported that the analogs at the lower end of the L-aspartyl-a-aminocycloalkanecarboxylic acid methyl ester series were sweet, the dipeptides containing a-... 

Aspartyl phenylalanine-l-methyl ester, better known as aspartame, is an artificial sweetener with a worldwide production exceeding 15 000 tpa. It is marketed under the trade names Nutrasweet, Canderel, and Equal. This dipeptide, made of aspartic... 

After the finding of a sweet taste in L-Asp-L-Phe-OMe (aspartame) by Mazur et at. (6), a number of aspartyl dipeptide esters were synthesized by several groups in order to deduce structure-taste relationships, and to obtain potent sweet peptides. In the case of the peptides, the configuration and the conformation of the molecule are important in connection with the space-filling properties. The preferred conformations of amino acids can be shown by application of the extended Hiickel theory calculation. However, projection of reasonable conformations for di- and tripeptide molecules is not easily accomplished. 

In the course of investigations of aspartyl dipeptide esters, we had to draw their chemical structures in a unified formula. In an attempt to find a convenient method for predicting the sweettasting property of new peptides and, in particular, to elucidate more definite structure-taste relationships for aspartyl dipeptide esters, we previously applied the Fischer projection technique in drawing sweet molecules in a unified formula 04). 

The sweet-tasting property of aspartyl dipeptide esters has been successfully explained on the basis of the general structures shown in Figure 1 (4). A peptide will taste sweet when it takes... 

Therefore, we have concluded that sweet-tasting aspartyl dipeptide esters can be drawn as the unified formula (A), whereas nonsweet peptides as (B) as shown in Figure 1. 

In Ama-L-Phe-OMe (47) (14, 15), it is also not known whether the sweet-tasting isomer has the L-L(or S-S) or the D-L(or R-S) configuration. In the case of aspartyl dipeptide esters, the L-L isomer was sweet. By analogy, other researchers deduced that the L-L(or S-S) isomer ((47b) in Figure 4) would be sweet. However, it seemed to us that the D(or i )-configuration would be preferred for the aminomalonic acid because the D-L(or R-S) isomer ((47a) in Figure 4) was compatible with the sweet formula and could also fit the spatial barrier model (13), whereas the L-L(or S-S) isomer could neither fit the receptor model nor meet the sweet formula. 

Further examinations of the molecular features and of the model of receptor have suggested that several aspartyl tripeptide esters may also taste sweet. In confirmation of the idea, several tripeptide esters have been synthesized. In the first place, L-Asp-Gly-Gly-OMe (38) was synthesized as an arbitrarily-selected standard of tripeptides, because it was considered that this peptide ester had the simplest structure, and correlation of other peptides to (38) was easy. The tripeptide ester was predicted that it would be slightly sweet or tasteless because its projection formula was similar in size and shape to that of L-Asp-Gly-0Bum which is 13 times sweeter than sucrose (16) and because it is more hydrophilic than the dipeptide. The tripeptide (38) was devoid of sweetness and almost tasteless. 

Finally, L-Asp-D-Val-Gly-OMe (41) was synthesized in order to see whether it remained sweet. The peptide was devoid of sweetness and almost tasteless, though D-valine-containing aspartyl dipeptide esters such as L-Asp-D-Val-0Pr (17) and L-Asp-D-Val-OPrt (8, 17), which are similar to the tripeptide ester in size and shape and have potent sweet taste. 

As mentioned above, the second amino acid of the sweet aspartyl dipeptide esters could be replaced by dipeptide esters... 

Aspartame is a dipeptide derivative, L-aspartyl-L-phenylalanine methyl ester, which was approved in the United States in 1981 for use as a tabletop sweetener, in dry beverage mixes, and in foods that are not heat processed. This substance is metabolized in the body to phenylalanine, aspartic acid, and methanol. Only people with phenylketonuria cannot break down phenylalanine. Another compound, diketopiperazine, may also be formed. However, no harmful effects from this compound have been demonstrated. The main limiting factor in the use of aspartame is its lack of heat stability (Homier 1984). 

---