Dipeptide Isosteres Research Articles

Copper-free defluorinative alkylation of allylic difluorides through Lewis acid-mediated C–F bond activation

The reactions of difluorohomoallyl alcohols with trialkylaluminiums smoothly proceeded in CH 2Cl 2 at room temperature to give ( Z)-fluoro-olefin products in excellent yields. On the basis of this chemistry, fluoro-olefinic dipeptide isostere of norvalinyl glycine was synthesized in stereoselective manner.

Copper mediated defluorinative allylic alkylation of difluorohomoallyl alcohol derivatives directed to an efficient synthetic method for ( Z)-fluoroalkene dipeptide isosteres

Difluoroallylation of optically pure O-silylated ( S)-2-methyl-3-hydroxypropanal 10a with bromodifluoropropene mediated by indium provided the corresponding difluorohomoallyl alcohol 11a with low diastereoselectivity, but without a decrease in optical purity. Defluorinative allylic alkylation of each diastereomer of the difluorohomoallyl alcohol efficiently proceeded by the reaction with trialkylaluminium and Cu(I) system or Grignard reagent and a catalytic amount of CuI system in THF to give the fluorine-substituted allylic alcohol 12 in an high yield and in an excellent Z selective manner. Subsequent imidate Claisen rearrangement of the allylic alcohol 12 proceeded with a complete 1,3-chirality transfer to give the fluoroalkene dipeptide isostere structure 14 after the final conversion of the primary alcohol 20 into the carboxylic acid form.

(3R,4R,5R)-5-(Acetamidomethyl)-N-benzyl-3,4-dihydroxytetrahydrofuran-3-carboxamide

X-ray crystallographic analysis with Cu Kα radiation established the relative configurations of the stereogenic centers in the title compound, C15H20N2O5, and clarified mechanistic ambiguities in the synthesis. The conformation of the five-membered ring approximates twisted, about a C—O bond. The absolute configuration of this carbon-branched dipeptide isostere was known based on the use of d-ribose as the starting material. Refinement of the Flack parameter gave an ambiguous result but the refined Hooft parameter is in agreement with the assumed (d-ribose) absolute structure. The crystal structure consists of N—H⋯O and O—H⋯O hydrogen-bonded bi-layers, with the terminal methyl and phenyl groups forming a hydro­phobic inter-layer inter­face. Some weak C—H⋯O inter­actions are also present.

ChemInform Abstract: A Convenient Approach to Hydroxyethylene Dipeptide Isosteres as Building Blocks for Enzyme Inhibitors.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Stereocontrolled Convergent Synthesis of Hydroxyethylene Dipeptide Isosteres by the Reaction of α-Amino Aldehyde with Alkoxytitanium Homoenolates.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis of Hydroxyethylene Dipeptide Isosteres That Mimic a Cyclic Amino Acid at the P1′ Subsite.

ChemInform Abstract: Synthesis of Hydroxyethylene Dipeptide Isosteres That Mimic a Cyclic Amino Acid at the P1′ Subsite.

ChemInform Abstract: Dipeptide Isosteres. Part 2. Synthesis of Hydroxyethylene Dipeptide Isostere Diastereomers from a Common γ-Lactone Intermediate. Preparation of Renin and HIV-1 Protease Inhibitor Transition State Mimics.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: A New Way to Diastereomeric Pure (E)-Alkene Dipeptide Isosters by Reaction of β-Aziridinyl-α,β-enoates with Organocopper Reagents.

ChemInform Abstract: A New Way to Diastereomeric Pure (E)-Alkene Dipeptide Isosters by Reaction of β-Aziridinyl-α,β-enoates with Organocopper Reagents.

ChemInform Abstract: Diastereoselective Synthesis of the Key Lactone Intermediate (VI) for the Preparation of Hydroxyethylene Dipeptide Isosteres.

ChemInform Abstract: Diastereoselective Synthesis of the Key Lactone Intermediate (VI) for the Preparation of Hydroxyethylene Dipeptide Isosteres.

ChemInform Abstract: Regiospecific Ring-Opening Reactions of β-Aziridinyl α,β-Enoates with Acids: Application to the Stereoselective Synthesis of a Couple of Diastereoisomeric (E)-Alkene Dipeptide Isosteres from a Single β-Aziridinyl α,β-Enoate and to the

Regio- and stereo-selective ring-opening reactions of N-(2,4,6-trimethylphenylsulfonyl)-γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-enoates with acids such as methanesulfonic acid (MSA) or trifluoroacetic acid (TFA) have been found. These ring-opening reactions are useful for the stereoselective synthesis of a couple of diastereomeric (E)-alkene dipeptide isosteres from a single substrate of γ,δ-epimino (E)-α,β-enoate, and for the convenient preparation of δ-aminated γ-hydroxy α,β-enoates.

ChemInform Abstract: Designing Secondary Structures: 5-Azidomethyl Tetrahydrofuran-2- Carboxylates as Carbohydrate-derived Dipeptide Isosteres

The potential of carbohydrate-like tetrahydrofuran frameworks as building blocks with predictable conformational propensities useful in the design and synthesis of novel peptidomimetic materials which adopt well-defined secondary structures is discussed.

ChemInform Abstract: Cyclopropane-Derived Peptidomimetics. Design, Synthesis, and Evaluation of Novel Enkephalin Analogues.

It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding cis-cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly2-Gly3 and Phe4-Leu5 dipeptide subunits in Leu-enkephalin (H2N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed to bind to opiod receptors in a conformation containing a β-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -XaaΨ[COcpCO]Yaa- and -XaaΨ[NHcpNH]Yaa-were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates catalyzed by the chiral rhodium complexes Rh2[(5S)-MEPY]4 and Rh2[(5R)-MEPY]4. A useful modification of the Weinreb amidation procedure was applied to the opening of the intermediate lactones with dipeptides, and a novel method for the syn...

ChemInform Abstract: Syntheses of Norstatine, Its Analogues, and Dipeptide Isosteres by Means of β-Lactam Synthon Method

ChemInform Abstract: Syntheses of Norstatine, Its Analogues, and Dipeptide Isosteres by Means of β-Lactam Synthon Method

Sugar amino acid based peptide epoxyketones as potential proteasome inhibitors

This paper describes the synthesis and biological evaluation of nine epoxomicin-derived sugar amino acid containing peptide epoxyketones. The title compounds are assembled from six sugar amino acid dipeptide isosteres and are synthesized using solution-phase peptide synthesis protocols. Although neither of the compounds displays inhibitory activity towards any of the proteasome active sites, our approach holds promise towards the development of structurally new proteasome inhibitors. It is likely that the central sugar amino acid dipeptide isoster needs to be designed such that it closely resemble dipeptides at position P2 and P3 in proteasome substrates inhibitors, such as the Thr-Ile dipeptide present in the lead compound, epoxomicin.

Gramicidin S Derivatives Containing cis‐ and trans‐Morpholine Amino Acids (MAAs) as Turn Mimetics

The cyclic decapeptide gramicidin S (GS) was used as a model for the evaluation of four turn mimetics. For this purpose, one of the D-Phe-Pro two-residue turn motifs in the rigid cyclic beta-hairpin structure of GS was replaced with morpholine amino acids (MAA 2-5), differing in stereochemistry and length of the side-chain. The conformational properties of the thus obtained GS analogues (6-9) was assessed by using NMR spectroscopy and X-ray crystallography, and correlated with their biological properties (antimicrobial and hemolytic activity). We show that compound 8, containing the dipeptide isostere trans-MAA 4, has an apparent high structural resemblance with GS and that its antibacterial activity against a panel of Gram positive and -negative bacterial strains is better than the derivatives 6, 7 and 9.

Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres

A set of cyclic peptide analogues of a selective CXCR4 antagonist FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)] were synthesized and bioevaluated. Using (E)-alkene and (Z)-fluoroalkene dipeptide isosteres for Arg-Arg and Arg-Nal substructures, indispensable or the partial contribution of the two peptide bonds to the CXCR4 antagonism and anti-HIV activity was demonstrated. FC131 and the analogues were shown to selectively inhibit SDF-1 binding to CXCR4, whereas no inhibition of binding of SDF-1 to CXCR7 was observed.

ChemInform Abstract: Amino Acid Based Synthesis of Trifluoromethylalkene Dipeptide Isosteres by Alcohol‐Assisted Nucleophilic Trifluoromethylation and Organozinc—Copper‐Mediated SN2′ Alkylation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A short approach to the synthesis of the ritonavir and lopinavir core and its C-3 epimer via cross metathesis

A short synthesis of hydroxyethylene dipeptide isostere, a core unit of the HIV-protease inhibitors ritonavir and lopinavir, its C-3 epimer and C 2 symmetric diamino diol is described. The crucial aspects of the synthesis are self-cross metathesis and exploitation of C 2-symmetric of the metathesis product 8 to obtain the required skeleton.

Structural and biological evaluation of some loloatin C analogues

Loloatin C is a cyclic cationic antimicrobial peptide which is active against Gram positive as well as certain Gram negative bacteria. Unfortunately, it is equally potent against human erythrocytes. To probe the structure–activity relationship of this promising antibiotic peptide, amino acid substitution and/or incorporation of a constraint sugar amino acid dipeptide isoster has been applied. Six new derivatives have been synthesized using SPPS and their solution structure investigated using NMR studies. Finally, the antimicrobial and the hemolytic activities have been determined.

Analogues of both Leu- and Met-enkephalin containing a constrained dipeptide isostere prepared from a Baylis-Hillman adduct

An efficient route was developed for the synthesis of the Fmoc-protected dipeptide 4, isostere of Gly-Gly containing an alpha-methylene beta-amino acid; the conformationally restricted analogues of Leu-enkephalin, 3a, and Met-enkephalin, 3b, respectively, were prepared by changing 4 for Gly(2)-Gly(3) in the native compounds 3a and 3b whose biological activities were significantly lower than the parent compounds.