6278-96-2Relevant academic research and scientific papers
Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile
Tran, Kien,Van Den Hauwe, Robin,Sainsily, Xavier,Couvineau, Pierre,C?té, Jér?me,Simard, Louise,Echevarria, Marco,Murza, Alexandre,Serre, Alexandra,Théroux, Léa,Saibi, Sabrina,Haroune, Lounès,Longpré, Jean-Michel,Lesur, Olivier,Auger-Messier, Mannix,Spino, Claude,Bouvier, Michel,Sarret, Philippe,Ballet, Steven,Marsault, éric
, p. 5345 - 5364 (2021/02/16)
Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.
An improved approach for the synthesis of α,α-dialkyl glycine derivatives by the Ugi-Passerini reaction
Costa, Susana P.G.,Maia, Hernani L.S.,Pereira-Lima, Silvia M.M.A.
, p. 1475 - 1479 (2007/10/03)
A general and simple strategy for routine peptide synthesis with α,α-dialkyl glycines taking advantage of the four-component Ugi-Passerini reaction is presented. The isonitrile required for the reaction can be relatively simple and its selection based on cost, as the group it generates is easily removed under acidic conditions; in addition, this removal is not visibly affected by the bulkiness of the α-alkyl groups. Being a good leaving group from the N-terminal amino group of the amino acid, 4-methoxybenzyl was the choice for the amine component of the reaction. The method is illustrated with the synthesis of a series of acyl derivatives of several α,α-dialkyl glycines. The preparation of the latter compounds is also reported.
Halo-substituted (S)-N-(2-benzoylphenyl)-1-benzylpyrolidine-2-carboxamides as new chiral auxiliaries for the asymmetric synthesis of (S)-α-amino acids
Belokon,Maleev,Petrosyan,Savel'eva,Ikonnikov,Peregudov,Khrustalev,Saghiyan
, p. 1593 - 1599 (2007/10/03)
The synthesis of new chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)-pyrrolidine-2-carboxamide (1a), (S)-N-(2-benzoylphenyl)-1-(pentafluorobenzyl)pyrrolidine-2-carboxamide (1b), and (S)-N-(2-benzoylphenyl)-1-(4-isopropoxytetrafluorobenzyl) pyrrolidine-2-carboxamide (1c) and their application in the asymmetric synthesis of amino acids using NiII complexes of their Schiff's bases with alanine and glycine are described. Compound la is particularly appropriate for highly stereoselective synthesis of α-methyl-α -amino acids with high enatiomeric purity (ee >95%).
Sterically hindered Cα,α-disubstituted α-amino acids: Synthesis from α-nitroacetate and incorporation into peptides
Fu,Hammarstroem,Miller,Fronczek,McLaughlin,Hammer
, p. 7118 - 7124 (2007/10/03)
The preparation of sterically hindered and polyfunctional Cα,α-disubstituted α-amino acids (ααAAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional Cα,α-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding Cα,α-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PYAOP/HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).
γ-Substituted pyrrole-based silyl dienol ethers as α-amino acid enolate equivalents: a versatile entry to racemic α-substituted α-amino acids
Zanardi, Franca,Battistini, Lucia,Rassu, Gloria,Cornia, Mara,Casiraghi, Giovanni
, p. 2471 - 2476 (2007/10/02)
γ-Substituted siloxypyrrole derivatives 5-7 have been synthesized by direct alkylation of N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole 1.These underwent subsequent alkylation with alkyl halides or aldehydes to produce γ,γ-disubstituted α,β-unsaturated lactam intermediates in good yields.Oxidative cleavage of the C(3)-C(4) bond within the lactam moiety gave rise to a number of α-substituted α-amino acids.These include racemic α-methylphenylalanine 14, α-benzylphenylalanine 15, α-benzylserine 18 and α-methylthreonine 21.
Furan-, pyrrole-, and thiophene-based siloxydienes for syntheses of densely functionalized homochiral compounds
Casiraghi,Rassu
, p. 607 - 626 (2007/10/02)
This review describes the methods of preparation and use of 2-(trimethylsiloxy)furan, N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsiloxy)pyrrole, and certain substituted analogues and congeners, including novel 2-(tert-butyldimethylsiloxy)thiophene, to synthesize complex carbohydrates, azasugars, polyhydroxylated alkaloids, C-glycosylated α-amino acids, amino acids bearing quaternary chiral carbon atoms, and thiosugars. Especially emphasized is the preparation of enantiomerically pure compounds of biological interest. Some mechanistic insights are presented.
SYNTHESIS OF α-SUBSTITUTED α-AMINO ACIDS BY THE ALKYLATION OF 5-OXAZOLINONE DERIVATIVES
Slavinskaya, V. A.,Sile, D. E.,Katkevich, M. Yu.,Korchagova, E. Kh.,Lukevits, E.
, p. 724 - 728 (2007/10/02)
Methods have been developed for the alkylation of 5-oxazolinone derivatives in DMF in the presence of K2CO3, KOH, or diisopropylethylamine and a phase transfer catalyst as well as for the preparation of α-methylphenylalanine, α-methylalanine, α-methylalanine, and the methyl ester of N-benzoyl-α-methylalanine.Increasing the initial concentration of the starting 5-oxazolinone in the reaction mixture leads to a sharp drop in the yield of reaction products due to side condensation reactions.The reaction of 2-phenyl-4-benzyl-5-oxazolinonewith ethyl iodide gave a dimer, mamely, 3-(benzoylamino)-3,5-dibenzylpyrrolidine-2,4-dione.
SOLID-LIQUID PHASE TRANSFER CATALYTIC SYNTHESIS OF α-AMINO ACID VIA ALKYLATION AND NUCLEOPHILIC ADDITION OF BENZALDEHYDE IMINES
Yaozhong, Jiang,Changyou, Zhou,Shengde, Wu,Daimo, Chen,Youan, Ma,Guilan, Liu
, p. 5343 - 5354 (2007/10/02)
A short, mild and efficient synthetic route of α-amino acid via alkylation, Michael addition and carbonyl addition as well as cycloaddition of aldimines derived from glycine and alanine esters with benzaldehyde under solid-liquid phase transfer catalytic condition has been studied.The key to solid-liquid phase transfer catalyzed reactions is the selection of a base for the various reactants.The yield is dependent on the base used.The results obtained using KOH, K2CO3 and Na2CO3 are discussed.The kinetics of solid-liquid PTC benzylation has been investigated and we propose a possible mechanism of solid-liquid PTC as an interface auto-catalytic procedure.The details of some syntheses of α-amino acids are presented.
