Synthesis Of Pseudopeptides Research Articles

ChemInform Abstract: Synthesis of Pseudopeptides with Sulfoximines as Chiral Backbone Modifying Elements.

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Solid‐Phase Synthesis of Pseudopeptides and Oligomeric Peptide Backbone Mimetics

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Synthesis of pseudopeptides with sulfoximines as chiral backbone modifying elements.

The synthesis of pseudopeptides with a chiral alpha-sulfonimidoylcarboxy moiety in the backbone is described. Starting from readily available (Ss)-S-methyl S-phenyl sulfoximine and various cyclic and acyclic alpha-amino acids the desired products are obtained in good yields with peptide coupling methodology. Specific secondary structures caused by intramolecular hydrogen bonds may be adopted. Results of NMR studies to reveal conformational preferences will be discussed.

Synthesis of the Novel Amino Acid 4-Amino-3-(aminomethyl)benzoic Acid (AmAbz) and Its Protected Derivatives as Building Blocks for Pseudopeptide Synthesis

Synthesis of the Novel Amino Acid 4-Amino-3-(aminomethyl)benzoic Acid (AmAbz) and Its Protected Derivatives as Building Blocks for Pseudopeptide Synthesis

Synthesis of the Novel Amino Acid 4-Amino-3-(aminomethyl)benzoic Acid (AmAbz) and Its Protected Derivatives as Building Blocks for Pseudopeptide Synthesis

4-Amino-3-(aminomethyl)benzoic acid (1) (AmAbz) is a novel unnatural amino acid with promise in applications as a building block for the synthesis of peptidomimetics and as a scaffold for combinatorial chemistry. It was efficiently synthesized in three steps (63% overall yield) from 4-aminobenzoic acid, by means of regioselective amidomethylation with hydroxymethylphthalimide. AmAbz (1) contains three distinct functionalities which could be discriminated from one another. Firstly, Boc2O or Fmoc−OSu reacted selectively with the benzylamino group to give the monoprotected derivatives AmAbz(Boc) (8a) or AmAbz(Fmoc) (8b), respectively. The absence of acylation at the arylamino group was also noticed in coupling experiments using the BOP reagent and building block 8b. This made protection of the arylamino group unnecessary either for peptide bond formation at the carboxyl group, or for subsequent elongation of a peptide chain at the benzylamino group. Finally, the arylamino group could be acylated under base-free, carbodiimide-mediated coupling conditions. These properties are illustrated by the solid-phase synthesis of the AmAbz-containing branched pseudopeptide Fmoc−Ala−Phe−AmAbz(H−Lys−Leu)−Val−Gly−NH2 (15). The synthesis of Fmoc−AmAbz(Boc) (10) is also described.

New Oxazole-Based Conformationally Restricted Peptidomimetics: Design and Synthesis of Pseudopeptides

New Oxazole-Based Conformationally Restricted Peptidomimetics: Design and Synthesis of Pseudopeptides

New Oxazole‐Based Conformationally Restricted Peptidomimetics: Design and Synthesis of Pseudopeptides

A general synthesis of a new class of optically active amino acids containing an oxazole moiety is described along with a strategy for their insertion into a peptidomimetic chain. A modified portion of endothelin-1 is prepared as a potential receptor antagonist. The procedure presented is based on readily available materials and can be performed in multigram quantities.

A versatile polymer-supported 4-(4-Methylphenyl(chloro)methyl)phenoxy linker for solid-phase synthesis of pseudopeptides

A versatile polymer-supported 4-(4-Methylphenyl(chloro)methyl)phenoxy linker for solid-phase synthesis of pseudopeptides

A versatile polymer-supported 4-(4-Methylphenyl(chloro)methyl)phenoxy linker for solid-phase synthesis of pseudopeptides

A versatile polymer-supported 4-(4-Methylphenyl(chloro)methyl)phenoxy linker for solid-phase synthesis of pseudopeptides

Design, synthesis, and evaluation of Phe-Gly mimetics: heterocyclic building blocks for pseudopeptides.

Enantiopure heterocyclic Boc-protected Phe-Gly dipeptidomimetics containing 1,3,4-oxadiazole, 1,2,4-oxadiazole, and 1,2,4-triazole ring systems have been synthesized as building blocks in the synthesis of pseudopeptides. Three derivatives (1-3) have the carboxylic acid function directly bound to the heterocyclic ring, and three derivatives (4-6) have an extra methylene group between the heterocyclic ring and the acid function to allow for an increased conformational flexibility. The mimetics were used as Phe-Gly replacements in the biologically active peptides dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH(2), SP). The pseudopeptide synthesis was performed using solid-phase methodology on a MBHA-resin using Boc-chemistry. The biological evaluation was performed by testing the micro- and delta-opioid receptor affinities of the dermorphin pseudopeptides and the NK(1) receptor affinities of the SP pseudopeptides. The results showed that all mimetics except 3 were excellent replacements of Phe-Gly in dermorphin since they displayed affinities for the micro-receptor (IC(50) = 12-31 nM) in the same range as dermorphin itself (IC(50) = 6.2 nM). The agonist activity of three pseudopeptides at human micro-receptors was also evaluated. It was shown that the tested compounds retained their agonist activity. The SP pseudopeptides showed considerably lower affinities (IC(50) > 1 microM) for the NK(1) receptor than SP itself (IC(50) = 1.5 nM) indicating that the Phe-Gly replacements prevent the pseudopeptides from adopting bioactive conformations.

Conformational Analysis of Peptides and Pseudopeptides Incorporating an endo-(2S,3R)-Norborn-5-ene Residue as a Turn Inducer

The synthesis of pseudopeptides 1−3 and peptide 4 were reported in the accompanying article. X-ray analysis of pseudopeptide 1 showed it to adopt a solid state conformation in which the Pro-Phe-Phe chain formed two consecutive β-turns, stabilized by hydrogen bonding between the Phe NH's and the norbornene carbonyls. However, NMR, IR, and CD studies showed that in CDCl3, CH2Cl2, and CH3CN solution, pseudopeptide 1 does not adopt a preferred conformation. A longer pseudopeptide 2 was found to exist in two different conformations in CDCl3 solution. The major conformer adopts a structure in which both tripeptide chains form a single β-turn which is stabilized by the formation of a hydrogen bond between the C-terminal amino acid NH and one of the norbornene carbonyls. In the minor conformer, however, the Pro-Phe-Phe chain forms two β-turns, analogous to the X-ray structure of pseudopeptide 1. The introduction of a urea unit into one of the peptide chains, as in pseudopeptide 3, offsets the atom positions so as...

A facile approach for the synthesis of pseudo-peptides incorporating a (2 S, 3 R)-2-amino-cyclopropane carboxylic acid residue

The synthesis of a pseudo-tripeptide 9 and a pseudo-pentapeptide 1 incorporating the conformationally constrained β-amino acid (2 S, 3 R)-2-amino cyclopropane carboxylic acid is reported. The key steps of the synthesis are the desymmetrisation of cyclopropane 1,2-dicarboxylic anhydride using ( S)-proline t-butyl ester followed by a Curtius rearrangement. Subsequent trapping of the isocyanate with ( S)-proline t-butyl ester or HN-( S)-Pro-( S)-Phe-( S)-Phe-OMe gave the desired pseudo-peptides. The stereochemistry of the desymmetrisation reaction was determined by X-ray crystallography of the amido-acid.

Synthetic studies towards proline amide isosteres, potentially useful molecules for biological investigations

2-Ethenylpyrrolidine derivative 8b was prepared from N-protected proline ethyl ester 6b. Bromofluorination of 8b with NBS-Bu 4NF/2HF gave a 1:1 regioisomeric mixture, 9b and 10b (X = Br). Dehydrobromination of 9b and 10b with t-BuOK produced a fluoroolefin 11 and a proline amide isostere model 12, respectively. Deprotection of the Z group in 12 was attempted by treatment with CF 3COOH. Although formation of the useful molecule in pseudopeptide synthesis, 13, was observed as checked by NMR spectra, it seemed to decompose slowly during purification procedure to give a mixture of fluorine-free compounds.

2-Bromoamides as synthons for pseudopeptides containing aminodicarboxy units

The monoalkylating and enantioselective behaviour of a chiral 2-bromoamide allows the synthesis of pseudopeptides in which a dipeptide component is changed into an aminodicarboxy moiety, with overall retention of configuration.

A Simple and Convenient Method for the Synthesis of Iminomethylene Analogs of Peptides

Abstract The synthesis of pseudopeptides in which a part of the peptide bonds has been replaced by other isosteric bonds has been studied in order to obtain long-lasting peptide drugs and also to study the structure-activity relationships of peptides with biological activity. A simple and convenient method for the synthesis of pseudo[CH2–NH]peptides was established by improving the conditions for the selective reduction of the peptide bond of N-protected dipeptide esters by borane. Among the ester residues investigated, the t-butyl ester gave the best result. During reactions no racemization occurred. [l-Pheψ[CH2–NH]l-Leu4−5]leucineenkephalin was synthesized in good yield starting from N-benzyloxycarbonyl-l-phenylalanyl-l-leucine t-butyl ester.

SYNTHESIS OF PSEUDOPEPTIDES

(1982). SYNTHESIS OF PSEUDOPEPTIDES. Organic Preparations and Procedures International: Vol. 14, No. 6, pp. 381-392.