New aspartame-like sweeteners containing L-(αMe)Phe

Polinelli, S.; Broxterman, Quirinus B.; Schoemaker, Hans E.; Boesten, W. H. J.; Crisma, Marco; Valle, G.; Toniolo, Claudio; Kamphuis, J.

doi:10.1016/s0960-894x(00)80168-7

Cited by 42 publications

(16 citation statements)

References 11 publications

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“…Figure 1a' shows the molecular model of aspartame in an extended conformation, whereas Figure 1b' shows the folded conformer of aspartame predicted by the Goodman's model. However, experimental structural studies were not sufficient to give an unequivocal answer, since the conformer found in the crystal structure of aspartame was consistent with Goodman's model, whereas that of the more rigid and sweeter [(L--Me)Phe 2 ] aspartame (Polinelli et al, 1992) was consistent with Temussi's one.…”

Section: Introductionmentioning

confidence: 80%

The history of sweet taste: not exactly a piece of cake

Temussi

2006

J of Molecular Recognition

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Understanding the molecular bases of sweet taste is of crucial importance not only in biotechnology but also for its medical implications, since an increasing number of people is affected by food-related diseases like, diabetes, hyperlipemia, caries, that are more or less directly linked to the secondary effects of sugar intake. Despite the interest paid to the field, it is only through the recent identification and functional expression of the receptor for sweet taste that new perspectives have been opened, drastically changing our approach to the development of new sweeteners. We shall give an overview of the field starting from the early days up to discussing the newest developments. After a review of early models of the active site, the mechanisms of interaction of small and macromolecular sweet molecules will be examined in the light of accurate modeling of the sweet taste receptor. The analysis of the homology models of all possible dimers allowed by combinations of the human T1R2 and T1R3 sequences of the sweet receptor and the closed (A) and open (B) conformations of the mGluR1 glutamate receptor shows that only 'type B' sites, either T1R2(B) and T1R3(B), can host the majority of small molecular weight sweeteners. Simultaneous binding to the A and B sites is not possible with two large sweeteners but is possible with a small molecule in site A and a large one in site B. This observation accounted for the first time for the peculiar phenomenon of synergy between some sweeteners. In addition to these two sites, the models showed an external binding site that can host sweet proteins.

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Section: Introductionmentioning

confidence: 80%

The history of sweet taste: not exactly a piece of cake

Temussi

2006

J of Molecular Recognition

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“…The crystal structure of the bitter L-ASP-D-(crMe)Phe-OMe was compared with the crystal structure of its sweet diastereomer L-Asp-L-(crMe)Phe-OMe [22]. Both compounds were found to assume extended conformations in the solid state.…”

Section: Discussionmentioning

confidence: 99%

“…The Xray structure corresponds to conformer I11 where the dihedral angles of the second residue are 42 = 49.0 and $2 = 47.9 for the X-ray structure and 42 = 53 and $2 = 49 for conformer 111. A comparison of the X-ray structures of L-ASP-D-(crMe)Phe-OMe, a bitter analogue, and that of its diastereoisomer L-Asp-L-(crMe)Phe-OMe [22], a sweet analogue, shows that they are essentially the same. In fact, the (crMe)Phe side chain in both diastereoisomers assumes the trans conformation about the C"-Cp bond: the relative orientation of the zwitterionic ring of the aspartyl moiety and the benzyl side chain, which are major groups for hydrophilic and hydrophobic interactions, respectively, is exactly the same.…”

Section: Ymentioning

confidence: 99%

Sweet and bitter taste: Structure and conformations of two aspartame dipeptide analogues

Benedetti¹,

Gavuzzo²,

Santini³

et al. 1995

Journal of Peptide Science

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The synthesis and X-ray diffraction analysis of two dipeptide taste ligands have been carried out as part of our study of the molecular basis of taste. The compounds L-aspartyl-D-alpha-methylphenylalanine methyl ester [L-Asp-D-(alpha Me)Phe-OMe] and L-aspartyl-D-alanyl-2,2,5, 5-tetramethylcyclopentanyl ester [L-Asp-D-Ala-OTMCP] elicit bitter and sweet taste, respectively. The C-terminal residues of the two analogues adopt distinctly different conformations in the solid state. The aspartyl moiety assumes the same conformation found in other dipeptide taste ligands with the side-chain carboxylate and the amino groups forming a zwitterionic ring with a conformation defined by psi, chi 1 = 157.7 degrees, -61.5 degrees for L-Asp-D-Ala-OTMCP and 151.0 degrees, -68.8 degrees for L-Asp-D-(alpha Me)Phe-OMe. In the second residue, a left-handed helical conformation is observed for the (alpha Me)Phe residue of L-Asp-D-(alpha Me)Phe-OMe with phi 2 = 49.0 degrees and psi 2 = 47.9 degrees, while the Ala residue of L-Asp-D-Ala-OTMCP adopts a semi-extended conformation characterized by dihedral angles phi 2 = 62.8 degrees and psi 2 = -139.9 degrees. The solid-state structure of the bitter L-Asp-D-(alpha Me)Phe-OMe is extended: while the crystal structure of the sweet L-Asp-D-OTMCP roughly adopts the typical L-shaped structure shown by other sweeteners. The data of L-Asp-D-(alpha Me)Phe-OMe are compared with those of its diastereoisomer L-Asp-L-(alpha Me)Phe-OMe. Conformational analysis of the two taste ligands in solution by NMR and computer simulations agrees well with our model for sweet and bitter tastes.

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“…Both the 5,5-disubstituted hydantoin and ring-opened Cadisubstituted amino acid derivatives of iminohydantoins 4 are of biological interest. [1][2][3][4][5] Thec onversion of E-a nd Z-4 into these targets,with preservation of the double bond geometry, was achieved by acidic hydrolysis of each of E-and Z-4a,c to give the corresponding hydantoins E-and Z-7a,c (Scheme 7). Oxidative removal of the p-methoxyphenyl group gave hydantoins E-a nd Z-8,w hich are unsaturated analogues of biologically active hydantoins (for example,m ephenytoin, phenytoin).…”

Section: Angewandte Chemiementioning

confidence: 99%

“…[2] Sterically constrained a,a-disubstituted a-amino acids (a-quaternary amino acids) are likewise important components of bioactive compounds,a nd their incorporation into peptides favors helical secondary structures [3] and offers increased resistance to chemical and enzymatic degradation. [4] In general, a-quaternary amino acids and their derivatives,s uch as biologically important 5,5-disubstituted hydantoins, [5] may be made from their tertiary counterparts by alkylation or rearrangement. [6] Furthermore,asmall number of transition-metal-catalyzed methods for the arylation of amino acid derived enolates have recently been developed.…”

mentioning

confidence: 99%

Geometry‐Retentive C‐Alkenylation of Lithiated α‐Aminonitriles: Quaternary α‐Alkenyl Amino Acids and Hydantoins

2017

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α-Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C-alkenylation on treatment with base by attack of the lithionitrile derivatives on the N'-alkenyl group. A geometry-retentive alkene shift affords stereospecifically the E or Z isomer of the 5-alkenyl-4-iminohydantoin products from the corresponding starting E- or Z-N'-alkenyl urea, each of which may be formed from the same N-allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp carbon atom, allows the direct regioselective incorporation of mono-, di-, tri-, and tetrasubstituted olefins at the α-carbon of amino acid derivatives. The initially formed 5-alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated α-quaternary amino acids.

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New aspartame-like sweeteners containing L-(αMe)Phe

Cited by 42 publications

References 11 publications

The history of sweet taste: not exactly a piece of cake

The history of sweet taste: not exactly a piece of cake

Sweet and bitter taste: Structure and conformations of two aspartame dipeptide analogues

Geometry‐Retentive C‐Alkenylation of Lithiated α‐Aminonitriles: Quaternary α‐Alkenyl Amino Acids and Hydantoins

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