RESUMO
Novel enantiopure pseudopeptide models containing a central -(ß-lactam)-(Aa)- scaffold characterized by the combined presence of an α-alkyl-α-amino-ß-lactam (i+1) residue and a α-substituted (i + 2) amino acid have been readily synthesized from α-alkyl serines. The conformational analysis of such ß-lactam pseudopeptides conducted in CDCl(3) and DMSO-d(6) solutions using 1D- and 2D-NMR techniques revealed an equilibrium between ß-II turn and γ-turn conformers, which was ultimately modulated by the relative configuration of the -(ß-lactam)-(Aa)- residues. Long-range chiral effects on the α-lactam pseudopeptide conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a central -(ß-lactam)-(Aib)- segment. In such mimetics, heterochiral (i) and (i + 3) residues reinforced a ß-II turn conformer, whereas homochiral corner residues stabilized an overlapped ß-II/ ß-I double turn motif. No ß-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, ß-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level, and finally, a conformation equilibrium model based on steric inter-residual interactions around the -(ß-lactam)-(i + 2)- segment was proposed to account for the observed chiral effects.
Assuntos
Peptídeos/química , beta-Lactamas/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
ß-Lactam peptides were envisioned as conformational constraints in antigenic peptides (APs). Three different ß-lactam tripeptides of varying flexibility were prepared in solution and incorporated in place of the central part of the altered melanoma associated antigenic peptide Leu(27)-Melan-A(26-35) using solid phase synthesis techniques. Upon TFA cleavage from the solid support, an unexpected opening of the ß-lactam ring occurred with conservation of the amide bond. After adaptation of the solid phase synthesis strategy, ß-lactam peptides were successfully obtained and both opened and closed forms were evaluated for their capacity to bind to the antigen-presenting class-I MHC HLA-A2 protein system. None of the closed ß-lactam peptides bound to HLA-A2, but their opened variants were shown to be moderate to good HLA-A2 ligands, one of them being even capable of stimulating a Melan-A-specific T cell line.
Assuntos
Ácidos/química , Antígeno HLA-A2/química , Peptídeos/síntese química , beta-Lactamas/química , Animais , Células Cultivadas , Cristalografia por Raios X , Antígeno HLA-A2/imunologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Peptídeos/imunologia , Linfócitos T/imunologiaRESUMO
New analogs of indole phytoalexin 1-methoxyspirobrassinol methyl ether have been designed by replacement of its 2-methoxy group with 2-(substituted phenyl)amino group. Synthesized by spirocyclization methodology, trans- and cis-diastereoisomers of target compounds were isolated and evaluated as potential anticancer and antimicrobial agents. Their molecular geometries were refined by ab initio minimizations. Pharmacophore modeling and QSAR studies were performed in order to correlate their molecular structure and biological activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Indóis/síntese química , Indóis/toxicidade , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Modelos Químicos , Relação Quantitativa Estrutura-Atividade , Sesquiterpenos , Estereoisomerismo , Terpenos/síntese química , Terpenos/química , FitoalexinasRESUMO
Hybrid glycopeptide beta-lactam mimetics designed to bind lectins or carbohydrate recognition domains in selectins have been prepared according to a "shape-modulating linker" design. This approach was implemented using the azide-alkyne "click" cycloaddition reaction, and as shown by NMR/MD experiments, binding of the resulting mimetics to Ulex Europaeus Lectin-1 (UEL-1) occurred after a "bent-to-extended" conformational change around a partially rotatable triazolylmethylene moiety.
Assuntos
Glicopeptídeos/química , Glicopeptídeos/farmacologia , Lectinas/antagonistas & inibidores , beta-Lactamas/química , beta-Lactamas/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Lectinas/química , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/química , Conformação Proteica , Ulex/químicaRESUMO
[reaction: see text] Ring opening of alpha-substituted-alpha-methoxycarbonyl-N-nosylaziridines provides a practical access to enantiopure alpha,alpha'-disubstituted beta-lactam scaffolds, novel types of ditopic reverse turn surrogates. The procedure is general, short, and high yielding and starts from handy alpha-substituted serinates and alpha-amino acid derivatives.
Assuntos
Materiais Biomiméticos/síntese química , Peptídeos/química , beta-Lactamas/química , Aziridinas/química , Materiais Biomiméticos/química , Estrutura Molecular , beta-Lactamas/síntese químicaAssuntos
Células Endoteliais/metabolismo , Lactamas/química , Peptídeos Cíclicos/química , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Integrina alfaVbeta3/metabolismo , Lactamas/síntese química , Lactamas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Peptidomiméticos , Transdução de SinaisRESUMO
Unsymmetrically 1,1'-disubstituted 4,4'-bis-1H-1,2,3-triazoles 4 have been prepared from 4-ethynyl-1,2,3-triazoles 5 and azides. Following a "double-click" strategy, two complementary approaches were implemented for the preparation of the key 4-ethynyltriazole intermediates 5: (a) the stepwise Swern oxidation/Ohira-Bestman alkynylation of readily available 4-hydroxymethyl-1,2,3-triazoles 8 and (b) the stepwise cycloaddition of TMS-1,4-butadiyne 9. The method is highlighted by its compatibility with orthogonally protected and functionalized saccharide-peptide hybrids and its ability to be extended to the trisubstituted counterparts 12.