Peptide sweeteners. 6. Structural studies on the C-terminal amino acid of L-aspartyl dipeptide sweeteners

Abstract

Stereochemical and structural aspects of the variations in the C-terminal residue of L-aspartyl-L-phenylalanine methyl ester have been investigated. Novel configurational analogues such as L-aspartyl-D-alanine benzyl ester and L-aspartyl-D-alpha-aminobutyric acid benzyl ester were found to be sweet. In addition, chiral and achiral alpha, alpha-dialkylglycine and alpha-aminocycloalkanecarboxylic acids were incorporated into the dipeptides. The L-aspartic acid based dipeptide derivatives of alpha-aminoisobutyric acid methyl ester, alpha-aminocyclopropanecarboxylic acid methyl ester, alpha-aminocyclobutanecarboxylic acid methyl ester, and alpha-aminocyclopentanecarboxylic acid methyl ester are sweet. Dipeptides with alpha-aminocyclohexanecarboxylic acid methyl ester and alpha-aminocycloheptanecarboxylic acid methyl ester are bitter, whereas the analogues with alpha-aminocyclooctanecarboxylic acid methyl ester, alpha, alpha-diethylglycine methyl ester, and alpha-aminoisobutyric acid benzyl ester are tasteless. Aspects on chirality and effective volume of the C-terminal residue are discussed and correlated with taste.

Linear oligopeptides. 188.Crystallographic characterization of the conformation of the 1-aminocyclopentane-1-carboxylic acid residue in simple derivatives

“…T o our knowledge, Acc5-containing peptides synthesized so far range from analogs of the formylmethionyl tripeptide chemoattractant (28-3 1) to the sweetening agent aspartame (32)(33)(34), from angiotensin I1 (35) to enkephalins (36,37), from the antitumor and antiviral agents 2,s-dioxopiperazines (38) to angiotensin-converting enzyme (39), peptidyltransferase (40), and y-glutamyl transpeptidase (41,42) inhibitors, from penicillin (43) and somatostatin (44) to oxytocin (45,46) and vasopressin (47).…”

1-Amino-3,3-difluorocyclobutanecarboxylic acid

“…Melting points are uncorrected. 1 H, 13 C and 19 F NMR spectra were recorded on a Varian Unity Plus 400 spectrometer (at 400.4, 100.7 and 376.7 MHz, respectively). Chemical shifts are reported in ppm downfield from TMS ( 1 H, 13 C) or CFCl 3 ( 19 F) as internal standards.…”

“…Organic phase was separated, dried over Na 2 SO 4 , and evaporated at reduced pressure to produce ketone 9 (1.68 g, 6.9 mmol, 100%) as a colourless oil. 1 O(CH 2 CH 2 ) 2 NSF 3 (1.40 g, 0.80 mmol, 2.2 eq.) was slowly added to a stirring solution of ketone 9 (900 mg, 3.7 mmol) in CH 2 Cl 2 (10 ml) at 0 8C.…”

“…1) gained considered interest in medicinal chemistry in recent years. ACBC was shown to increase enzymatic stability of peptides, influence their biological properties [1,2], and promote certain peptide conformations [3,4]. Furthermore, ACBC moiety was found to be crucial for the activity of some aldose reductase inhibitors [5], as well as NK 1 antagonists [6].…”

Conformational analysis of the dipeptide taste ligandL-aspartyl-D-2-aminobutyric acid-(S)-α-ethylbenzylamide and its analogues by NMR spectroscopy, computer simulations and X-ray diffraction studies

“…The discovery of aspartame [3], a dipeptide with potent sweet taste (approximately 200 times more potent than sucrose), stimulated extensive structure-activity relationship studies [4,5]. The structure of aspartame is Asp-Phe-OMe, where the protonated amino and carboxylate groups of the Nterminal aspartic acid residue have been proposed to be the AH and B groups of the Shallenberger and Acree model, respectively.…”