Dipeptide amides

FIGURE 8.6 Synthesis of /V-protccted dipeptide amides (A) and methylamides (B) by ami-nolysis of the unisolated succinimido ester obtained through the mixed anhydride in CH2C12.22 The products contained <0.5% of epimerized compound. HONSu = /V-hydroxysuccinimde, NMM = Af-methylmorpholine. 

Li H, Flinspach ML, Igarashi J, Jamal J, Yang W, Gomez-Vidal JA, Litzinger EA, Huang H, Erdal EP, Silverman RB, Poulos TP. Exploring the binding conformations of bulkier dipeptide amide inhibitors in constitutive nitric oxide synthases. Biochemistry 2005 44 15222-15229. 

Huang H, Martasek P, Roman LJ, Masters BS, Silverman RB. f2-nitroarginine-containing dipeptide amides. Potent and highly selective inhibitors of neuronal nitric oxide synthase. J. Med. 

Peptidomimetic ligands for opioid receptors have also been identified from combinatorial libraries. Screening of an N-(substi-tuted)glycine peptoid library for affinity for ix opioid receptors yielded novel structures (251) with high affinity for these receptors (K = 6-46 nM) (953). A library of dipeptide amides with alkyl substituents on both the interior and C-terminal amides were prepared, and high affinity agonists for all three opioid receptors identified from the library (see Ref 946). Peptide libraries can also be further modified ["libraries from libraries" (954)] to yield new potential ligands for receptors. Thus an acety-... 

A different type of peptide hydrolase, dipeptide transferase, catalyzed the oligomerization of dipeptide amides. In the case of glycyl-L-tyrosinamide, the corresponding oligomer with DP up to 8 was formed.242... 

A remarkably simple one-step synthesis of a peptide receptor in 13% yield has been reported by Yoon and Still (Figure 69) [94], This molecule was shown to bind y-acylated amino acids and dipeptide amides with high enantioselectivity. For example, L- and D-enantiomers of N-Boc-Gly-Val-NHMe (Boc=t-butoxycarbonyl, Val = valine) showed complexation free energies of... 

Goodman, M., Coddington, J., and Mierke, D.F. (1987). A model for the sweet taste of stereoisomeric retro-inverso and dipeptide amides. J. Amer. Chem. Soc. 109, 4712-4714. 

The protease Carboxypeptidase Y (CPD-Y) reacts with the tyrosine ester forming an acylenzyme activated complex, which is further converted in a competitive way. Aminolysis of the acylenzyme by Arg-NH2 (2) yields the dipeptide amide Tyr-Arg-NH2. The competing hydrolysis (1) yields the non-activated tyrosine. The dipeptide amide Tyr-Arg-NH2 is deamidated selectively by peptide amidase (PA) to the desired... 

A new sweetener, named Alitame by its inventors in your Research Division, is a dipeptide amide of L-aspartic acid and D-alanine. In contrast, aspartame, the amino acid-based sweetener currently approved by the FDA, is a dipeptide ester and contains L-phenylalanine instead of D-alanine. The New Products Department has tested the new material in a variety of uses and claims that it is stable enough for use in baked goods and has a longer shelf life than aspartame. It is also 12 times as sweet as aspartame and would not be harmful to people with the metabolic disorder, phenylketonuria, who must limit the intake of substances containing phenylalanine. Use is projected in foods, beverages, toiletries, and pharmaceuticals. 

Portlock and co-workers have demonstrated the sequential use of a Petasis borono-Mannich reaction and an Ugi 4-component coupling reaction for the generation of dipeptide amides 24 (Scheme 7.6) [45]. Exchange of the solvent from dichloro-methane to MeOH was required between the Petasis borono-Mannich and Ugi reac-... 

Scheme 7.6 Sequential use of Petasis borono-Mannich and Ugi 4-component coupling reactions for the generation of dipeptide amides.

The biuret reaction is best suited for detection of peptides three amino acid residues and longer but, nonetheless, a number of dipeptides are detectable at reasonable potentials [156]. Although N-terminal dipeptide amides require a high pH (pH 12) for Cu(II) complexation, they are detected at relatively low potentials (-+0.50 V vs. Ag/AgCl). In comparison, C-terminal dipeptide amides exhibit a... 

Table 8.11. Taste of some dipeptide amides of the type L-Asp-D-Ala-NHR...

The stability of dipeptide amides of the alitame type is substantially higher than that of dipeptide esters of the aspartame type. Therefore, alitame can also be used in bread and confectionery. 

Glowaky, R.C., Hendrick, M.E., Smiles, R.E., Torres, A. Development and uses of AUtame A novel dipeptide amide sweetener ACS Symposium Series 450, p. 57 (1991)... 

Halophilic microorganisms that evolved to survive low water activity conditions are promising for the discovery of peptidases that survive under harsh conditions. A halophilic serine peptidase from Halobacterium salinarum was reported to catalyze the synthesis of di- and tripeptides, for example producing Ac-Phe-Gly-Leu-NH from Ac-Phe-OEt as acyl donor in 76% yield in the presence of 33% (v/v) DMF, 20 equivalenfs of the nucleophile dipeptide amide, and 2.8 M NaCl [80]. The acyl donor specificity of fhe enzyme is quite broad, but the nucleophile preferred at SI is Gly, Ala, or another small hydrophobic group. Although promising, the synthetic potential of halophilic peptidases is still poorly exploited, and biochemical information on such enzymes is scarce. 

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