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1.
J Org Chem ; 85(3): 1513-1524, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31769989

RESUMO

Peptides are well-known to play a fundamental therapeutic role and to represent building blocks for numerous useful biomaterials. Stabilizing their active 3D-structure by appropriate modifications remains, however, a challenge. In this study, we have expanded the available literature information on the conformational propensities of a promising backbone change of a terminally blocked δ-amino acid residue, a dipeptide mimic, by replacing its central amide moiety with an (E) Cß═Cγ alkene unit. Specifically, we have examined by DFT calculations, X-ray diffraction in the crystalline state, and FT-IR absorption/NMR spectroscopies in solution the extended vs folded preferences of analogues of this prototype system either unmodified or possessing single or multiple methyl group substituents on each of its four -CH2-CH═CH-CH2- main-chain carbon atoms. The theoretical and experimental results obtained clearly point to the conclusion that increasing the number of adequately positioned methylations will enhance the preference of the original sequence to fold, thus opening interesting perspectives in the design of conformationally constrained peptidomimetics.

2.
Chemistry ; 25(50): 11758-11764, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31215086

RESUMO

Peptide sequences functionalized with primary amines at the N- and C-terminus are able to induce the aggregation of gold nanoparticles in ethanol as a consequence of their folding into a helical conformation. Random coil peptides are unable to induce such an aggregation process. Aggregation can be monitored spectrophotometrically by following the shift of the surface plasmon resonance (SPR) band of the nanoparticles and is confirmed by transmission electron microscopy and dynamic light scattering analyses. Partial denaturation of the peptides results in diminished cross-linking ability. The helicity parameter θ222 /θ208 correlates fairly well with the shift of the SPR band to longer wavelengths, supporting the relationship between the amount of helical content of a peptide sequence and its ability to induce aggregation.

3.
Org Lett ; 21(11): 4182-4186, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31090420

RESUMO

Systems in which an external stimulus elicits a response through some sort of modification at the molecular or supramolecular level bear potential for the development of smart materials and devices. This work describes a versatile synthetic approach suitable for the stepwise incorporation of multiple, even consecutive, units of the simplest Cα,ß-unsaturated ß-amino acid, ( E/ Z)-3-aminoprop-2-enoic acid, in peptide-based foldamers. The properties of these, including photoinduced E/ Z isomerizations, were investigated.

4.
Angew Chem Int Ed Engl ; 57(32): 10217-10220, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29944774

RESUMO

A simple, unsaturated, E-Z photoisomerizable ß-amino acid, (Z)-3-aminoprop-2-enoic acid, has been introduced into peptide foldamers through a one-pot chemical coupling, based on Pd/Cu-catalyzed olefin oxidative amidation, between two peptide segments carrying, respectively, a -Gly-NH2 residue at the C-terminus and an acryloyl group at the N-terminus. Reversible conversion between the Z and E configurations of the 3-aminoprop-2-enoic linkage was achieved photochemically. A crystallographic analysis on two model compounds shed light on the consequences, in terms of 3D structure and self-association properties, brought about by the different configuration of the unsaturated linkage. As a proof of concept, E-Z photoisomerization of a 3-aminoprop-2-enoic acid residue, inserted as the junction between two conformationally distinct peptide domains (one helical while the other ß-sheet promoter), allowed supramolecular self-association to be reversibly turned on/off.


Assuntos
Peptídeos/química , Cristalografia por Raios X , Modelos Moleculares , Processos Fotoquímicos , Conformação Proteica , Dobramento de Proteína
5.
J Phys Chem Lett ; 8(10): 2236-2242, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28471190

RESUMO

The controversial nature of the fluorescent properties of carbon dots (CDs), ascribed either to surface states or to small molecules adsorbed onto the carbon nanostructures, is an unresolved issue. To date, an accurate picture of CDs and an exhaustive structure-property correlation are still lacking. Using two unconventional spectroscopic techniques, fluorescence correlation spectroscopy (FCS) and time-resolved electron paramagnetic resonance (TREPR), we contribute to fill this gap. Although electron micrographs indicate the presence of carbon cores, FCS reveals that the emission properties of CDs are based neither on those cores nor on molecular species linked to them, but rather on free molecules. TREPR provides deeper insights into the structure of carbon cores, where C sp2 domains are embedded within C sp3 scaffolds. FCS and TREPR prove to be powerful techniques, characterizing CDs as inherently heterogeneous systems, providing insights into the nature of such systems and paving the way to standardization of these nanomaterials.

6.
Soft Matter ; 13(23): 4231-4240, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28509927

RESUMO

Two appropriately functionalized nucleobases, thymine and adenine, have been covalently linked at the N- and C-termini, respectively, of two α-aminoisobutyric acid-rich helical peptide foldamers, aiming at driving self-assembly through complementary recognition. A crystal-state analysis (by X-ray diffraction) on the shorter, achiral foldamer 1 unambiguously shows that adeninethymine base pairing, through Watson-Crick intermolecular H-bonding, does take place between either end of each peptide molecule. In the crystals, π-stacking between base pairs is also observed. Evidence for time-dependent foldameroldamer associations for the longer, chiral foldamer 2 in solution is provided by circular dichroism measurements. The self-assembly of foldamer 2, through living supramolecular polymerization, eventually leads to the formation of twisted fibers. Such a supramolecular organization can be affected by addition of either pristine adenine or thymine, that acts as a "terminator" by selectively matching a pairing nucleobase at one end of the foldamer. The co-assembly of foldamer 2 with a porphyrin-derivatized thymine, under appropriate experimental conditions, leads to the formation of vesicles which, in turn, can be converted to the fiber morphology by changing the environmental polarity. Conversely, dendrimeric, star polymer-like microstructures are generated when the supramolecular assembly of foldamer 2 is seeded by adenine-capped gold nanoparticles.

7.
J Phys Chem B ; 121(17): 4379-4387, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28422504

RESUMO

We address the interpretation, via an integrated computational approach, of the experimental continuous-wave electron paramagnetic resonance (cw-EPR) spectra of a complete set of conformationally highly restricted, stable 310-helical peptides from hexa- to nonamers, each bis-labeled with nitroxide radical-containing TOAC (4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-4-carboxylic acid) residues. The usefulness of TOAC for this type of analysis has been shown already to be due to its cyclic piperidine side chain, which is rigidly connected to the peptide backbone α-carbon. The TOAC α-amino acids are separated by two, three, four, and five intervening residues. This set of compounds has allowed us to modulate both the radical···radical distance and the relative orientation parameters. To further validate our conclusion, a comparative analysis has been carried out on three singly TOAC-labeled peptides of similar main-chain length.


Assuntos
Óxidos N-Cíclicos/química , Óxidos de Nitrogênio/química , Peptídeos/química , Teoria Quântica , Espectroscopia de Ressonância de Spin Eletrônica , Marcadores de Spin
8.
Chem Phys Lipids ; 204: 43-56, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28300538

RESUMO

Bile acid synthesis defects are rare genetic disorders characterized by a failure to produce normal bile acids (BAs), and by an accumulation of unusual and intermediary cholanoids. Measurements of cholanoids in urine samples by mass spectrometry are a gold standard for the diagnosis of these diseases. In this work improved methods for the chemical synthesis of 30 BAs conjugated with glycine, taurine and sulfate were developed. Diethyl phosphorocyanidate (DEPC) and diphenyl phosphoryl azide (DPPA) were used as coupling reagents for glycine and taurine conjugation. Sulfated BAs were obtained by sulfur trioxide-triethylamine complex (SO3-TEA) as sulfating agent and thereafter conjugated with glycine and taurine. All products were characterized by NMR, IR spectroscopy and high resolution mass spectrometry (HRMS). The use of these compounds as internal standards allows an improved accuracy of both identification and quantification of urinary bile acids.


Assuntos
Ácidos e Sais Biliares/urina , Glicina/química , Erros Inatos do Metabolismo/urina , Sulfatos/química , Taurina/química , Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/normas , Glicina/normas , Humanos , Conformação Molecular , Espectrometria de Massas por Ionização por Electrospray/normas , Sulfatos/normas , Espectrometria de Massas em Tandem/normas , Taurina/normas
9.
J Pept Sci ; 23(4): 346-362, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28004461

RESUMO

We performed the solution-phase synthesis of a set of model peptides, including homo-oligomers, based on the 2-aminoadamantane-2-carboxylic acid (Adm) residue, an extremely bulky, highly lipophilic, tricyclic, achiral, Cα -tetrasubstituted α-amino acid. In particular, for the difficult peptide coupling reaction between two Adm residues, we took advantage of the Meldal's α-azidoacyl chloride approach. Most of the synthesized Adm peptides were characterized by single-crystal X-ray diffraction analyses. The results indicate a significant propensity for the Adm residue to adopt γ-turn and γ-turn-like conformations. Interestingly, we found that a -CO-(Adm)2 -NH- sequence is folded in the crystal state into a regular, incipient γ-helix, at variance with the behavior of all of the homo-dipeptides from Cα -tetrasubstituted α-amino acids already investigated, which tend to adopt either the ß-turn or the fully extended conformation. Our density functional theory conformational energy calculations on the terminally blocked homo-peptides (n = 2-8) fully confirmed the crystal-state data, strongly supporting the view that this rigid Cα -tetrasubstituted α-amino acid residue is largely the most effective building block for γ-helix induction, although to a limited length (anti-cooperative effect). Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.


Assuntos
Peptídeos/química , Cristalografia por Raios X , Modelos Moleculares , Peptídeos/síntese química , Conformação Proteica , Teoria Quântica , Soluções
10.
J Pept Sci ; 23(2): 155-161, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27862690

RESUMO

A symmetrical dipeptide-based diacetylene system (DAs) was found to be able to self-assemble in dichloromethane and to form a compact fiber network which resulted in a stable organogel. As a consequence of the organogel formation, we explored the possibility to run a light-induced topochemical polymerization. This is a typical reaction of ordered diacetylene moieties taking advantage from their organized packing mode resulting from fiber formation. Evidence for the generation of peptide-based polydiacetylenes is provided by Raman, UV-Vis, and CD spectroscopies and a set of microscopic techniques. Finally, we succeeded in processing a polymeric composite by use of the electrospinning technique, starting from a mixture of a dipeptide-based diacetylene and polymethyl methacrylate. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.


Assuntos
Dipeptídeos/química , Polímeros/química , Polimetil Metacrilato/química , Poli-Inos/química , Técnicas Eletroquímicas , Géis , Luz , Processos Fotoquímicos , Polímero Poliacetilênico , Polimerização
11.
Phys Chem Chem Phys ; 18(45): 31286-31295, 2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27824179

RESUMO

The design of novel nanostructures with tailored opto-electronic properties is a crucial step for third-generation photovoltaics, and the development of cheap and environmentally compatible materials is still a challenge. Carbon quantum dots (CQDs) emerged as promising candidates but usually a low processability and poor electron-donor properties hampered their photovoltaic applications. We tackle these issues through the synthesis and photophysical characterization of N-doped CQDs functionalized with different thiophene-containing groups. Functionalization was aimed at enhancing the electron donating properties of the carbon dots and improving the solubility in nonpolar solvents. The increased solubility in organic solvents allowed us to investigate the photoinduced interactions of the functionalized carbon dots with the fullerene derivative PCBM in solution and in solid blends. The investigation was carried out by cyclic voltammetry, photoluminescence spectroscopy and electron paramagnetic resonance (EPR). The remarkable oxidation potential shift of the functionalized carbon dots with respect to the pristine materials and the HOMO-LUMO energies strongly suggest them as good electron donors towards PCBM. The electron transfer process between CQDs and PCBM resulted in efficient fluorescence quenching in solution and in total quenching in solid blends. By using EPR spectroscopy in the solid blends, we demonstrated the efficient electron transfer by observing the photoinduced formation of a PCBM radical anion in the presence of functionalized CQDs. Time-resolved EPR allowed us to identify differences in the charge transport efficiency for different CQD:PCBM blends. The enhanced processability of CQDs with PCBM and the promising charge-generation and separation properties pave the way to the development of "all-carbon" photovoltaic devices.

12.
J Am Chem Soc ; 138(32): 10151-6, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27437555

RESUMO

On-surface synthesis involving the homocoupling of aryl-alkynes affords the buildup of bisacetylene derivatives directly at surfaces, which in turn may be further used as ingredients for the production of novel functional materials. Generally, homocoupling of terminal alkynes takes place by thermal activation of molecular precursors on metal surfaces. However, the interaction of alkynes with surface metal atoms often induces unwanted reaction pathways when thermal energy is provided to the system. In this contribution we report about light-induced metal-free homocoupling of terminal alkynes on highly oriented pyrolitic graphite (HOPG). The reaction occurred with high efficiency and selectivity within a self-assembled monolayer (SAM) of aryl-alkynes and led to the generation of large domains of ordered butadiynyl derivatives. Such a photochemical uncatalyzed pathway represents an original approach in the field of topological C-C coupling at the solid/liquid interface.

13.
J Am Chem Soc ; 138(25): 8007-18, 2016 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-27258674

RESUMO

An E unsaturated fumaramide linkage may be introduced into Aib peptide foldamer structures by standard coupling methods and photoisomerized to its Z (maleamide) isomer by irradiation with UV light. As a result of the photoisomerization, a new hydrogen-bonded contact becomes possible between the peptide domains located on either side of the unsaturated linkage. Using the fumaramide/maleamide linker to couple a chiral and an achiral fragment allows the change in hydrogen bond network to communicate a conformational preference, inducing a screw sense preference in the achiral domain of the maleamide-linked foldamers that is absent from the fumaramides. Evidence for the induced screw sense preference is provided by NMR and CD, and also by the turning on by light of the diastereoselectivity of a peptide chain extension reaction. The fumaramide/maleamide linker thus acts as a "conformational photodiode" that conducts stereochemical information as a result of irradiation by UV light.

14.
Soft Matter ; 12(1): 238-45, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26463728

RESUMO

A terminally protected, hydrophobic dipeptide Boc-L-Cys(Me)-L-Leu-OMe (1) was synthesized and its 3D-structure was determined by single crystal X-ray diffraction analysis. This peptide is able to hierarchically self-assemble in a variety of superstructures, including hollow rods, ranging from the nano- to the macroscale, and organogels. In addition, 1 is able to drive fullerene (C60) or multiwalled carbon nanotubes (MWCNTs) in an organogel by co-assembling with them. A hybrid 1-C60­MWCNT organogel was prepared and converted (through a high vacuum-drying process) into a robust, high-volume, water insoluble, solid material where C60 is well dispersed over the entire superstructure. This ternary material was successfully tested as a catalyst for: (i) the reduction reaction of water-soluble azo compounds mediated by NaBH4 and UV-light with an overall performance remarkably better than that provided by C60 alone, and (ii) the NaBH4-mediated reduction of benzoic acid to benzyl alcohol. Our results suggest that the self-assembly properties of 1 might be related to the occurrence in its single crystal structure of a sixfold screw axis, a feature shared by most of the linear peptides known so far to give rise to nanotubes.


Assuntos
Dipeptídeos/química , Fulerenos/química , Nanotubos/química , Ácido Benzoico/química , Álcool Benzílico/química , Boroidretos/química , Catálise , Cristalização , Cisteína/análogos & derivados , Leucina/análogos & derivados , Oxirredução
15.
ChemMedChem ; 11(2): 217-33, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26381330

RESUMO

There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative to the parent compound and no increase in atom count. Optimization of 17 led to compounds with nanomolar cellular activity.


Assuntos
Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Termodinâmica , Triazinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Quinase Syk , Triazinas/síntese química , Triazinas/química
16.
Eur J Med Chem ; 108: 553-563, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26717205

RESUMO

Herein is described the synthesis of novel glycine-α-methyl-proline-containing tripeptides (GP(Me)X tripeptides namely GP(Me)R, GP(Me)K, and GP(Me)H) with the aim of obtaining derivatives highly stable in human plasma and able to counteract neuroinflammatory processes that are distinctive of neurodegenerative pathologies. The syntheses of GP(Me)R, GP(Me)K, and GP(Me)H were all achieved both by introducing the Pro(Me) residue into the Gly-Pro-Arg (GPR) sequence in place of the native Pro in P2 position and replacing the basic amino acid Arg in P3 position by Lys or His. Results showed that all novel GP(Me)X tripeptides are stable in human plasma (t1/2 > 51 h) and that GP(Me)H - generating stable intramolecular H-bond in a C11-turn by interaction of His imidazole ring and Gly carbonyl group - restored physiological levels of nitric oxide deriving from neuronal NOS (nNOS) activity, thus preventing the inflammatory response by suppression of the NF-kB activity and, consequently, the expression of inflammatory genes such as inducibile NOS (iNOS). Therefore, GP(Me)H could be a lead compound for further development of peptidomimetics able to contrast neuroinflammatory processes.


Assuntos
Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Neurônios/citologia , Neurônios/patologia , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/química , Oligopeptídeos/sangue , Oligopeptídeos/química , Prolina/sangue , Prolina/química , Prolina/farmacologia , Relação Estrutura-Atividade
17.
Chemistry ; 21(40): 13866-77, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26243713

RESUMO

Among the various types of α-peptide folding motifs, δ-turn, which requires a central cis-amide disposition, has been one of the least extensively investigated. In particular, this main-chain reversal topology has been studied in-depth neither in linear/cyclic peptides nor in proteins. This Minireview article assembles and critically analyzes relevant data from a literature survey on the δ-turn conformation in those compounds. Unpublished results from recent conformational energy calculations and a preliminary solution-state analysis on a small model peptide, currently ongoing in our laboratories, are also briefly outlined.


Assuntos
Peptídeos Cíclicos/química , Peptídeos/química , Proteínas/química , Peptídeos/metabolismo , Conformação Proteica , Estrutura Terciária de Proteína , Proteínas/metabolismo , Inquéritos e Questionários , Temperatura
18.
J Org Chem ; 80(11): 5507-16, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25938852

RESUMO

A new α,α-disubstituted constrained glutamine analogue has been designed to decorate gold nanoparticles and to induce a 310-helix when inserted in peptides. Using an efficient "one-pot" asymmetric Schmidt reaction between 4-disubstituted-cyclohexanone and hydroxyalkylazides, 1H-azepine-2-oxo-5-amino-5-carboxylic acid was prepared. The main (R) isomer was inserted at the N-terminus in a very short peptide sequence (i.e., PhCO-(R)-Oxo-Azn-L-Ala-Aib-L-AlaNHMe) and a stable 310-helix conformation was obtained, as verified by both NMR experiments and molecular dynamics (MD) simulations. Finally, the presence of the hydroxyl chain at the nitrogen atom of the ring allowed for the preparation of covered chiral gold nanoparticles.


Assuntos
Azepinas/química , Ácidos Carboxílicos/síntese química , Ouro/química , Nanopartículas/química , Peptídeos/química , Sequência de Aminoácidos , Azepinas/síntese química , Ácidos Carboxílicos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estereoisomerismo
19.
ACS Nano ; 9(4): 4156-64, 2015 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-25772001

RESUMO

Herein, we propose convenient routes to produce hybrid-polymers that covalently enclosed, or confined, N-doped carbon quantum dots (CQDs). We focus our attention on polyamide, polyurea-urethane, polyester, and polymethylmetacrylate polymers, some of the most common resources used to create everyday materials. These hybrid materials can be easily prepared and processed to obtain macroscopic objects of different shapes, i.e., fibers, transparent sheets, and bulky forms, where the characteristic luminescence properties of the native N-doped CQDs are preserved. More importantly we explore the potential use of these hybrid composites to achieve photochemical reactions as those of photoreduction of silver ions to silver nanoparticles (under UV-light), the selective photo-oxidation of benzylalcohol to the benzaldehyde (under vis-light), and the photocatalytic generation of H2 (under UV-light).

20.
J Pept Sci ; 21(3): 148-77, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25640955

RESUMO

In this second part of our review article on the preferred screw sense and interconversion of peptide helices, we discuss the most significant computational and experimental data published on helices formed by the most extensively investigated categories of noncoded α-amino acids. They are as follows: (i) N-alkylated Gly residues (peptoids), (ii) C(α) -alkylated α-amino acids, (iii) C(α,ß) -sp(2) configurated α-amino acids, and (iv) combinations of residues of types (ii) and (iii). With confidence, the large body of interesting papers examined and classified in this editorial effort will stimulate the development of helical peptides in many diverse areas of biosciences and nanosciences.


Assuntos
Aminoácidos/química , Peptídeos/química , Peptidomiméticos/química , Peptoides/química , Alquilação , Aminoácidos/síntese química , Cristalografia por Raios X , Código Genético , Cinética , Ressonância Magnética Nuclear Biomolecular , Peptídeos/síntese química , Peptidomiméticos/síntese química , Peptoides/síntese química , Estrutura Secundária de Proteína , Termodinâmica
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