Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802425

RESUMO

Supramolecular peptide hydrogels are gaining increased attention, owing to their potential in a variety of biomedical applications. Their physical properties are similar to those of the extracellular matrix (ECM), which is key to their applications in the cell culture of specialized cells, tissue engineering, skin regeneration, and wound healing. The structure of these hydrogels usually consists of a di- or tripeptide capped on the N-terminus with a hydrophobic aromatic group, such as Fmoc or naphthalene. Although these peptide conjugates can offer advantages over other types of gelators such as cross-linked polymers, they usually possess the limitation of being particularly sensitive to proteolysis by endogenous proteases. One of the strategies reported that can overcome this barrier is to use a peptidomimetic strategy, in which natural amino acids are switched for non-proteinogenic analogues, such as D-amino acids, ß-amino acids, or dehydroamino acids. Such peptides usually possess much greater resistance to enzymatic hydrolysis. Peptides containing dehydroamino acids, i.e., dehydropeptides, are particularly interesting, as the presence of the double bond also introduces a conformational restraint to the peptide backbone, resulting in (often predictable) changes to the secondary structure of the peptide. This review focuses on peptide hydrogels and related nanostructures, where α,ß-didehydro-α-amino acids have been successfully incorporated into the structure of peptide hydrogelators, and the resulting properties are discussed in terms of their potential biomedical applications. Where appropriate, their properties are compared with those of the corresponding peptide hydrogelator composed of canonical amino acids. In a wider context, we consider the presence of dehydroamino acids in natural compounds and medicinally important compounds as well as their limitations, and we consider some of the synthetic strategies for obtaining dehydropeptides. Finally, we consider the future direction for this research area.


Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Nanoestruturas/química , Peptídeos/química , Peptidomiméticos/química , Aminoácidos/química , Animais , Humanos , Estrutura Secundária de Proteína
2.
Nanomaterials (Basel) ; 11(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799670

RESUMO

Short peptides capped on the N-terminus with aromatic groups are often able to form supramolecular hydrogels, via self-assembly, in aqueous media. The rheological properties of these readily tunable hydrogels resemble those of the extracellular matrix (ECM) and therefore have potential for various biological applications, such as tissue engineering, biosensors, 3D bioprinting, drug delivery systems and wound dressings. We herein report a new photo-responsive supramolecular hydrogel based on a "caged" dehydropeptide (CNB-Phe-ΔPhe-OH 2), containing a photo-cleavable carboxy-2-nitrobenzyl (CNB) group. We have characterized this hydrogel using a range of techniques. Irradiation with UV light cleaves the pendant aromatic capping group, to liberate the corresponding uncaged model dehydropeptide (H-Phe-ΔPhe-OH 3), a process which was investigated by 1H NMR and HPLC studies. Crucially, this cleavage of the capping group is accompanied by dissolution of the hydrogel (studied visually and by fluorescence spectroscopy), as the delicate balance of intramolecular interactions within the hydrogel structure is disrupted. Hydrogels which can be disassembled non-invasively with temporal and spatial control have great potential for specialized on-demand drug release systems, wound dressing materials and various topical treatments. Both 2 and 3 were found to be non-cytotoxic to the human keratinocyte cell line, HaCaT. The UV-responsive hydrogel system reported here is complementary to previously reported related UV-responsive systems, which are generally composed of peptides formed from canonical amino acids, which are susceptible to enzymatic proteolysis in vivo. This system is based on a dehydrodipeptide structure which is known to confer proteolytic resistance. We have investigated the ability of the photo-activated system to accelerate the release of the antibiotic, ciprofloxacin, as well as some other small model drug compounds. We have also conducted some initial studies towards skin-related applications. Moreover, this model system could potentially be adapted for on-demand "self-delivery", through the uncaging of known biologically active dehydrodipeptides.

3.
Soft Matter ; 16(44): 10001-10012, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-32789370

RESUMO

The development of strategies to minimise the adverse side-effects of non-steroidal anti-inflammatory drugs (NSAIDs) remains a challenge for medicinal chemists. One such strategy is the development of NSAID-peptide prodrug conjugates and this conjugation to a peptide often confers the additional property of hydrogelation. This review summarises the work published by our research group, alongside other research groups, on supramolecular hydrogels consisting of short peptides conjugated to NSAIDs. Generally, supramolecular low molecular weight hydrogels (LMWHs) are composed of amphiteric molecules, usually consisting of short peptides attached to an aromatic capping group. When the aromatic capping group is switched for an NSAID to afford hybrid gelators, some conjugates exhibit retained or improved anti-inflammatory properties of the parent drug, and sometimes new and unexpected biological activities are observed. Conjugation to peptides often provides selective COX-2 inhibition over COX-1 inhibtion, which is key to retaining the anti-inflammatory benefits of NSAIDs whilst minimising gastric side-effects. Naproxen is the most commonly employed NSAID capping group, partly due to its similarity in structure to commonly employed naphthalene capping groups. Biomimetic approaches, where canonical amino acids are switched for non-natural amino acids such as d-amino acids or dehydroamino acids, are often employed, to tune the stability. The future direction for this area of research is discussed.

4.
Pharmaceutics ; 12(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028608

RESUMO

The use of peptide-drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen-dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen-dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.

5.
Nanomaterials (Basel) ; 9(4)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987203

RESUMO

Self-assembled peptide hydrogels have emerged in recent years as the new paradigm in biomaterials research. We have contributed to this field the development of hydrogels based on dehydrodipeptides N-capped with naproxen. The dehydrodipeptide hydrogels can be loaded with drugs, thus being potential nanocarriers for drug delivery. In this work novel dehydrodipeptides containing tyrosine and aspartic acid amino acid residues N-capped with naproxen and C-terminal dehydrophenylalanine were prepared and characterized. Superparamagnetic iron oxide nanoparticles (SPIONs) were incorporated into the dehydrodipeptide-based hydrogels and their effect on the self-assembly, structure and rheological and magnetic properties of the hydrogels was studied. Magnetic hydrogels, with incorporated SPIONs, displayed concentration-dependent T2-MRI contrast enhancement. Moreover, upon magnetic excitation (alternating magnetic field -AMF-) the SPIONs were able to generate a significant amount of heat. Hence, magnetic hyperthermia can be used as a remote trigger for release of drug cargos and SPIONs incorporated into the self-assembled dehydrodipeptide hydrogels.

6.
Chemistry ; 23(41): 9772-9789, 2017 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-28444700

RESUMO

Functional porphyrins have attracted intense attention due to their remarkably high extinction coefficients in the visible region and potential for optical and energy-related applications. Two new routes to functionalised SWNTs have been established using a bulky ZnII -porphyrin featuring thiolate groups at the periphery. We probed the optical properties of this zinc(II)-substituted, bulky aryl porphyrin and those of the corresponding new nano-composites with single walled carbon nanotube (SWNTs) and coronene, as a model for graphene. We report hereby on: i) the supramolecular interactions between the pristine SWNTs and ZnII -porphyrin by virtue of π-π stacking, and ii) a novel covalent binding strategy based on the Bingel reaction. The functional porphyrins used acted as dispersing agent for the SWNTs and the resulting nanohybrids showed improved dispersibility in common organic solvents. The synthesized hybrid materials were probed by various characterisation techniques, leading to the prediction that supramolecular polymerisation and host-guest functionalities control the fluorescence emission intensity and fluorescence lifetime properties. For the first time, XPS studies highlighted the differences in covalent versus non-covalent attachments of functional metalloporphyrins to SWNTs. Gas-phase DFT calculations indicated that the ZnII -porphyrin interacts non-covalently with SWNTs to form a donor-acceptor complex. The covalent attachment of the porphyrin chromophore to the surface of SWNTs affects the absorption and emission properties of the hybrid system to a greater extent than in the case of the supramolecular functionalisation of the SWNTs. This represents a synthetic challenge as well as an opportunity in the design of functional nanohybrids for future sensing and optoelectronic applications.

7.
J Mater Chem B ; 5(43): 8607-8617, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-32264529

RESUMO

Peptide-based self-assembled hydrogels have triggered remarkable research interest in recent years owing to their biocompatibility and biomimetic properties and responsiveness, which warrant many technological and biomedical applications. Dehydrodipeptides N-capped with naproxen emerged from our research as effective hydrogelators endowed with resistance to proteolysis. Dehydrodipeptide-based hydrogels are promising nanocarriers for drug delivery applications. In this work, we demonstrate that dehydrodipetide Npx-l-Ala-Z-ΔPhe-OH can be deployed as a minimalist hydrogelator module for synthesizing a gelating construct Npx-l-Ala-Z-ΔPhe-G-R-G-D-G-OH bearing a GRGDG adhesion motif. The self-assembly of the peptide construct and the drug delivery properties of the hydrogel were studied in this work. The peptide construct showed no toxicity towards a fibroblast cell line expressing the αvß3 integrin. Docking studies suggest that the hydrogelator block does not interfere with the recognition of the RGD motif by the integrin receptor. The self-assembly seems to be directed by intermolecular naphthalene π-π stacking interactions, with the peptide backbone assuming a random coil conformation both in solution and in the gel phase. TEM and STEM imaging revealed that the hydrogel is made of entangled bundles of long thin fibres (width circa 23 nm). The hydrogel exhibits viscoelastic properties, thermo-reversibility and recovery after mechanical fluidization. FRET studies showed that curcumin incorporated into the hydrogel interacts non-covalently with the hydrogel fibrils. Delivery of curcumin from the hydrogel into Nile red loaded model membranes (SUVs) was demonstrated by FRET. Naproxen N-capped dehydrodipeptides are efficacious minimalist hydrogelator modules for obtaining hydrogels functionalized with peptide ligands for cell receptors. These hydrogels are potential nanocarriers for drug delivery.

8.
Hum Vaccin Immunother ; 12(2): 491-502, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26360663

RESUMO

A single vaccination of Yellow Fever vaccines is believed to confer life-long protection. In this study, results of vaccinees who received a single dose of 17DD-YF immunization followed over 10 y challenge this premise. YF-neutralizing antibodies, subsets of memory T and B cells as well as cytokine-producing lymphocytes were evaluated in groups of adults before (NVday0) and after (PVday30-45, PVyear1-4, PVyear5-9, PVyear10-11, PVyear12-13) 17DD-YF primary vaccination. YF-neutralizing antibodies decrease significantly from PVyear1-4 to PVyear12-13 as compared to PVday30-45, and the seropositivity rates (PRNT≥2.9Log10mIU/mL) become critical (lower than 90%) beyond PVyear5-9. YF-specific memory phenotypes (effector T-cells and classical B-cells) significantly increase at PVday30-45 as compared to naïve baseline. Moreover, these phenotypes tend to decrease at PVyear10-11 as compared to PVday30-45. Decreasing levels of TNF-α(+) and IFN-γ(+) produced by CD4(+) and CD8(+) T-cells along with increasing levels of IL-10(+)CD4(+)T-cells were characteristic of anti-YF response over time. Systems biology profiling represented by hierarchic networks revealed that while the naïve baseline is characterized by independent micro-nets, primary vaccinees displayed an imbricate network with essential role of central and effector CD8(+) memory T-cell responses. Any putative limitations of this cross-sectional study will certainly be answered by the ongoing longitudinal population-based investigation. Overall, our data support the current Brazilian national immunization policy guidelines that recommend one booster dose 10 y after primary 17DD-YF vaccination.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Brasil , Humanos , Memória Imunológica/imunologia , Interferon gama/sangue , Fator de Necrose Tumoral alfa/sangue , Vacinação , Febre Amarela/virologia
9.
Biomacromolecules ; 16(11): 3562-73, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26443892

RESUMO

In this work, we introduce dipeptides containing tryptophan N-capped with the nonsteroidal anti-inflammatory drug naproxen and C-terminal dehydroamino acids, dehydrophenylalanine (ΔPhe), dehydroaminobutyric acid (ΔAbu), and dehydroalanine (ΔAla) as efficacious protease resistant hydrogelators. Optimized conditions for gel formation are reported. Transmission electron microscopy experiments revealed that the hydrogels consist of networks of micro/nanosized fibers formed by peptide self-assembly. Fluorescence and circular dichroism spectroscopy indicate that the self-assembly process is driven by stacking interactions of the aromatic groups. The naphthalene groups of the naproxen moieties are highly organized in the fibers through chiral stacking. Rheological experiments demonstrated that the most hydrophobic peptide (containing C-terminal ΔPhe) formed more elastic gels at lower critical gelation concentrations. This gel revealed irreversible breakup, while the C-terminal ΔAbu and ΔAla gels, although less elastic, exhibited structural recovery and partial healing of the elastic properties. A potential antitumor thieno[3,2-b]pyridine derivative was incorporated (noncovalently) into the gel formed by the hydrogelator containing C-terminal ΔPhe residue. Fluorescence and Förster resonance energy transfer measurements indicate that the drug is located in a hydrophobic environment, near/associated with the peptide fibers, establishing this type of hydrogel as a good drug-nanocarrier candidate.


Assuntos
Portadores de Fármacos/química , Hidrogéis/química , Naproxeno/química , Triptofano/química , Alanina/análogos & derivados , Alanina/química , Linhagem Celular Tumoral , Dicroísmo Circular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Microscopia Eletrônica de Transmissão , Modelos Teóricos , Naftalenos/química , Fenilalanina/análogos & derivados , Fenilalanina/química , Reologia
10.
Dalton Trans ; 44(9): 4016-31, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25611006

RESUMO

The relaxivity displayed by Gd(3+) chelates immobilized onto gold nanoparticles is the result of the complex interplay between the nanoparticle size, the water exchange rate and the chelate structure. In this work we study the effect of the length of ω-thioalkyl linkers, anchoring fast water exchanging Gd(3+) chelates onto gold nanoparticles, on the relaxivity of the immobilized chelates. Gold nanoparticles functionalized with Gd(3+) chelates of mercaptoundecanoyl and lipoyl amide conjugates of the DO3A-N-(α-amino)propionate chelator were prepared and studied as potential CA for MRI. High relaxivities per chelate, of the order of magnitude 28-38 mM(-1) s(-1) (30 MHz, 25 °C), were attained thanks to simultaneous optimization of the rotational correlation time and of the water exchange rate. Fast local rotational motions of the immobilized chelates around connecting linkers (internal flexibility) still limit the attainable relaxivity. The degree of internal flexibility of the immobilized chelates seems not to be correlated with the length of the connecting linkers. Biodistribution and MRI studies in mice suggest that the in vivo behavior of the gold nanoparticles was determined mainly by size. Small nanoparticles (HD = 3.9 nm) undergo fast renal clearance and avoidance of the RES organs while larger nanoparticles (HD = 4.8 nm) undergo predominantly hepatobiliary excretion. High relaxivities, allied to chelate and nanoparticle stability and fast renal clearance in vivo suggest that functionalized gold nanoparticles hold great potential for further investigation as MRI contrast agents. This study contributes to a better understanding of the effect of linker length on the relaxivity of gold nanoparticles functionalized with Gd(3+) complexes. It is a relevant contribution towards "design rules" for nanostructures functionalized with Gd(3+) chelates as Contrast Agents for MRI and multimodal imaging.


Assuntos
Quelantes/química , Meios de Contraste/química , Complexos de Coordenação/química , Gadolínio/química , Ouro/química , Nanopartículas Metálicas/química , Animais , Quelantes/farmacocinética , Meios de Contraste/farmacocinética , Complexos de Coordenação/farmacocinética , Gadolínio/farmacocinética , Ouro/farmacocinética , Masculino , Camundongos , Ratos Wistar , Distribuição Tecidual , Água/química
11.
Dalton Trans ; 43(21): 8037-47, 2014 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-24718365

RESUMO

The availability of commercial (68)Ge/(68)Ga cyclotron-independent (68)Ga(3+) generators is making Positron Emission Tomography (PET) accessible to most hospitals, which is generating a surge of interest in the design and synthesis of bi-functional chelators for Ga(3+). In this work we introduce the NO2A-N-(α-amino)propionic acid family of chelators based on the triazacyclononane scaffold. Complexation of the parent NO2A-N-(α-amino)propionic acid chelator and of a low molecular weight (model) amide conjugate with Ga(3+) was studied by (1)H and (71)Ga NMR. The Ga(3+) chelate of the amide conjugate shows pH-independent N3O3 coordination in the pH range 3-10 involving the carboxylate group of the pendant propionate arm in a 6 member chelate. For the Ga[NO2A-N-(α-amino)propionate] chelate, a reversible pH-triggered switch from Ga(3+) coordination to the carboxylate group to coordination to the amine group of the propionate arm was observed upon pH increase/decrease in the pH range 4-6. This phenomenon can conceivably constitute the basis of a physiological pH sensor. Both complexes are stable in the physiological range. The [(67)Ga][NO2A-N-(α-benzoylamido)propionate] chelate was found to be stable in human serum. Biodistribution studies of the (67)Ga(3+)-labeled pyrene butyric acid conjugate NO2A-N-(α-pyrenebutanamido)propionic acid revealed that, despite its high lipophilicity and concentration-dependent aggregation properties, the chelate follows mainly renal elimination with very low liver/spleen accumulation and no activity deposition in bones after 24 hours. Facile synthesis of amide conjugates of the NO2A-N-(α-amino)propionic acid chelator, serum stability of the Ga(3+) chelates and fast renal elimination warrant further evaluation of this novel class of chelators for PET applications.


Assuntos
Amidas/química , Quelantes/química , Gálio/química , Tomografia por Emissão de Pósitrons/métodos , Propionatos/química , Animais , Quelantes/síntese química , Quelantes/farmacocinética , Gálio/farmacocinética , Radioisótopos de Gálio/química , Radioisótopos de Gálio/farmacocinética , Humanos , Propionatos/síntese química , Propionatos/farmacocinética , Ratos Wistar
12.
Contrast Media Mol Imaging ; 8(1): 40-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23109391

RESUMO

A novel synthetic methodology for preparing amide conjugates of the DO3A-N-(α-amino)propionate chelator is described, using the synthesis of the DO3A-N-(α-benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N-(α-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+). The Gd[DO3A-N-(α-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A-N-(α-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents.


Assuntos
Quelantes , Meios de Contraste , Compostos Heterocíclicos com 1 Anel , Imagem por Ressonância Magnética/métodos , Animais , Quelantes/síntese química , Quelantes/química , Quelantes/farmacologia , Meios de Contraste/síntese química , Meios de Contraste/química , Meios de Contraste/farmacologia , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Concentração de Íons de Hidrogênio , Ligantes , Masculino , Ratos , Ratos Wistar , Zinco/química
13.
J Org Chem ; 76(23): 9584-92, 2011 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-22017265

RESUMO

A new expeditious preparation of homochiral (-)-1-azafagomine and (+)-5-epi-1-azafagomine has been devised. Stoodley's diastereoselective cycloaddition of dienes bearing a 2,3,4,6-tetraacetyl glucosyl chiral auxiliary to 4-phenyl-1,2,4-triazole-3,5-dione was merged with Bols's protocol for functionalizing alkenes into molecules bearing a glucosyl framework. Homochiral (+)-5-epi-1-azafagomine was synthetized for the first time. Partial reductive cleavage of the phenyltriazolidinone moiety afforded new homochiral 1-N-phenyl carboxamide derivatives of 1-azafagomine. Both enantiomers of these derivatives were synthetized and tested, displaying a very good enzymatic inhibition toward baker's yeast α-glucosidase. The molecular recognition mechanism of the 1-N-phenyl carboxamide derivative of 1-azafagomine by α-glucosidase from baker's yeast was studied by molecular modeling. The efficient packing of the aromatic ring of the 1-N-phenyl carboxamide moiety into a hydrophobic subsite (pocket) in the enzyme's active site seems to be responsible for the improved binding affinity in relation to underivatized (-)-1-azafagomine and (+)-1-azafagomine.


Assuntos
Amidas/química , Inibidores Enzimáticos/síntese química , Indolizinas/síntese química , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Ciclização , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Indolizinas/química , Indolizinas/farmacologia , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade
14.
J Biol Inorg Chem ; 16(5): 725-34, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21461972

RESUMO

The study of ligand-receptor interactions using high-resolution NMR techniques, namely the saturation transfer difference (STD), is presented for the recognition process between La(III) complexes of 1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane monoamide and diethylenetriaminepentaacetic acid bisamide glycoconjugates and the galactose-specific lectin Ricinus communis agglutinin (RCA(120)). This new class of Gd(III)-based potential targeted MRI contrast agents (CAs), bearing one or two terminal sugar (galactosyl or lactosyl) moieties, has been designed for in vivo binding to the asialoglycoprotein receptor, which is specifically expressed at the surface of liver hepatocytes, with the aim of leading to a new possible diagnosis of liver diseases. The in vitro affinity constants for the affinity of the divalent La(III)-glycoconjugate complexes for RCA(120), used as a simple, water-soluble receptor model, were higher than those of the monovalent analogues. The combination of the experimental data obtained from the STD NMR experiments with molecular modelling protocols (Autodock 4.1) allowed us to predict the mode of binding of monovalent and divalent forms of these CAs to the galactose 1α binding sites of RCA(120). The atomic details of the molecular interactions allowed us to corroborate and supported the interaction of both sugar moieties and the linkers with the surface of the protein and, thus, their contribution to the observed interaction stabilities.


Assuntos
Glicoconjugados/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Lantânio/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Ácido Pentético/química , Lectinas de Plantas/metabolismo , Ricinus/química , Meios de Contraste/química , Meios de Contraste/metabolismo , Glicoconjugados/química , Compostos Heterocíclicos com 1 Anel/metabolismo , Lantânio/química , Modelos Moleculares , Ácido Pentético/metabolismo , Lectinas de Plantas/isolamento & purificação , Ligação Proteica , Ricinus/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-20044301

RESUMO

Piroxicam (PRX) has been widely studied in an attempt to elucidate the causes and mechanisms of its side effects, mainly the photo-toxicity. In this paper fluorescence spectra in non-protic solvents and different polarities were carried out along with theoretical calculations. Preliminary potential surfaces of the keto and enol forms were obtained at AM1 level of theory providing the most stable conformers, which had their structure re-optimized through the B3LYP/CEP-31G(d,p) method. From the optimized structures, the electronic spectra were calculated using the TD-DFT method in vacuum and including the solvent effect through the PCM method and a single water molecule near PRX. A new potential surface was constructed to the enol tautomer at DFT level and the most stable conformers were submitted to the QST2 calculations. The experimental data showed that in apolar media, the solution fluorescence is raised. Based on conformational analysis for the two tautomers, keto and enol, the results indicated that the PRX-enol is the main tautomer related to the drug fluorescence, which is reinforced by the spectra results, as well as the interconvertion barrier obtained from the QST2 calculations. The results suggest that the PRX one of the enol conformers presents great possibility of involvement in the photo-toxicity mechanisms.


Assuntos
Modelos Teóricos , Conformação Molecular , Piroxicam/química , Espectrometria de Fluorescência , Modelos Químicos , Modelos Moleculares , Teoria Quântica , Soluções , Água
16.
Chem Commun (Camb) ; (42): 6475-7, 2009 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-19841814

RESUMO

We report the synthesis of a novel, versatile and easily accessible metal chelator, DO3A-N-alpha-aminopropionate, and the relaxometric characterization of its Gd(3+) complex, revealing great potential for the development of high relaxivity targeted contrast agents for magnetic resonance imaging.


Assuntos
Meios de Contraste/síntese química , Gadolínio/química , Imagem por Ressonância Magnética , Compostos Organometálicos/síntese química , Água/química , Meios de Contraste/química , Compostos Organometálicos/química
17.
Dalton Trans ; (24): 4656-70, 2009 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-19513474

RESUMO

A novel bis-hydroxymethyl-substituted DTTA chelator N'-Bz-C(4,4')-(CH(2)OH)(2)-DTTA () and its DTPA analogue C(4,4')-(CH(2)OH)(2)-DTPA () were synthesized and characterized. A variable-temperature (1)H NMR spectroscopy study of the solution dynamics of their diamagnetic (La) and paramagnetic (Sm, Eu) Ln(3+) complexes showed them to be rigid when compared with analogous Ln(3+)-DTTA and Ln(3+)-DTPA complexes, as a result of their C(4,4')-(CH(2)OH)(2) ligand backbone substitution. The parameters that govern the water (1)H relaxivity of the [Gd()(H(2)O)(2)](-) and [Gd()(H(2)O)](2-) complexes were obtained by (17)O and (1)H NMR relaxometry. While the relaxometric behaviour of the [Gd()(H(2)O)](2-) complex is very similar to the parent [Gd(DTPA)(H(2)O)](2-) system, the [Gd()(H(2)O)(2)](-) complex displays higher relaxivity, due to the presence of two inner sphere water molecules and an accelerated, near optimal water exchange rate. The [Gd()(H(2)O)(2)](-) complex interacts weakly with human serum albumin (HSA), and its fully bound relaxivity is limited by slow water exchange, as monitored by (1)H NMR relaxometry. This complex interacts weakly with phosphate, but does not form ternary complexes with bidentate bicarbonate and l-lactate anions, indicating that the two inner-sphere water molecules of the [Gd()(H(2)O)(2)](-) complex are not located in adjacent positions in the coordination sphere of the Gd(3+) ion. The transmetallation reaction rate of [Gd()(H(2)O)(2)](-) with Zn(2+) in phosphate buffer solution (pH 7.0) was measured to be similar to that of the backbone unsubstituted [Gd(DTTA-Me)(H(2)O)(2)](-), but twice faster than for [Gd(DTPA-BMA)(H(2)O)]. The in vivo biodistribution studies of the (153)Sm(3+)-labelled ligand () in Wistar rats reveal slow blood elimination and short term fixation in various organs, indicating some dissociation. The bis-hydroxymethyl-substituted DTTA skeleton can be seen as a new lead for the synthesis of high relaxivity contrast agents, although its low thermodynamic and kinetic stability will limit its use to in vitro and animal studies.


Assuntos
Meios de Contraste/química , Elementos da Série dos Lantanídeos/química , Imagem por Ressonância Magnética , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Animais , Ânions/química , Quelantes/química , Quelantes/metabolismo , Quelantes/farmacocinética , Meios de Contraste/metabolismo , Meios de Contraste/farmacocinética , Gadolínio/química , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ácido Pentético/metabolismo , Ácido Pentético/farmacocinética , Ligação Proteica , Ratos , Ratos Wistar , Albumina Sérica/química , Albumina Sérica/metabolismo , Distribuição Tecidual , Água/química , Zinco/química
18.
NMR Biomed ; 21(4): 322-36, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17694538

RESUMO

The recently reported amphiphilic chelate, [Gd(EPTPAC16)(H2O)]2-, forms supramolecular aggregates in aqueous solution by self-assembly of the monomers with a relaxometrically determined critical micellar concentration (CMC) of 0.34 mM. The effect of sonication on the aggregate size was characterized by dynamic light scattering and relaxometry, indicating the presence of premicellar aggregates and an overall decrease in aggregate size and polydispersity upon sonication, slightly below the CMC. [[153Sm](EPTPAC16)(H2O)]2- radiotracer was evaluated in vivo from gamma scintigraphy and biodistribution in Wistar rats. It was found to depend strongly on the sample concentration, below or above the CMC, and its sonication, in a way that correlates with the effect of the same factors on the size of the aggregates formed in solution. Below CMC, the very large aggregates of the [153Sm]3+ -labeled chelate were persistently and mainly taken up by the lungs, and also by the macrophage-rich liver and spleen. Sonication of this solution led to loss of the lung uptake. Above CMC, the metal chelate was mainly taken up by the liver, with very little uptake by the spleen and lungs. In vivo, dynamic contrast-enhanced (DCE)-MRI evaluation of the micellar [Gd(EPTPAC16)(H2O)]2- compound in Wistar rats showed a persistent hepatic positive-contrast effect in T1-weighted images, qualitatively similar to the clinically established Gd(III)-based hepatobiliary-selective agents. No enhancement effect was observed in the lungs because of the scarcity of mobile protons in this organ, despite the scintigraphic evidence of significant lung retention of the [153Sm]3+ -labeled chelate at concentrations below the CMC.


Assuntos
Quelantes/farmacologia , Meios de Contraste/farmacologia , Imageamento Tridimensional/métodos , Fígado/metabolismo , Compostos Organometálicos/farmacologia , Animais , Quelantes/química , Quelantes/farmacocinética , Meios de Contraste/química , Meios de Contraste/farmacocinética , Luz , Fígado/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Cintilografia , Ratos , Ratos Wistar , Espalhamento de Radiação , Soluções , Sonicação , Fatores de Tempo , Distribuição Tecidual/efeitos dos fármacos , Água
19.
Biomacromolecules ; 8(2): 392-8, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17291062

RESUMO

The amphiphilic molecule dextrin-VA-SC16 (dexC16) was synthesized and studied in this work. DexC16 has a hydrophilic dextrin backbone with grafted acrylate groups (VA) substituted with hydrophobic 1-hexadecanethiol (C16). A versatile synthetic method was developed allowing control of the dextrin degree of substitution with the hydrophobic chains (DSC16, number of alkyl chains per 100 dextrin glucopyranoside residues). Materials with different DSC16 were prepared and characterized using 1H NMR. DexC16 self-assembles in water through association of the hydrophobic alkyl chains, originating nanoparticles. The nanoparticles properties were studied by dynamic light scattering (DLS), fluorescence spectroscopy, and atomic force microscopy (AFM).


Assuntos
Dextrinas/química , Nanopartículas , Compostos de Sulfidrila/química , Acrilatos , Dimerização , Interações Hidrofóbicas e Hidrofílicas , Análise Espectral
20.
J Pharm Biomed Anal ; 40(1): 51-5, 2006 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-16102931

RESUMO

A multivariate method of analysis of nystatin and metronidazole in a semi-solid matrix, based on diffuse reflectance NIR measurements and partial least squares regression, is reported. The product, a vaginal cream used in the antifungal and antibacterial treatment, is usually, quantitatively analyzed through microbiological tests (nystatin) and HPLC technique (metronidazole), according to pharmacopeial procedures. However, near infrared spectroscopy has demonstrated to be a valuable tool for content determination, given the rapidity and scope of the method. In the present study, it was successfully applied in the prediction of nystatin (even in low concentrations, ca. 0.3-0.4%, w/w, which is around 100,000 IU/5g) and metronidazole contents, as demonstrated by some figures of merit, namely linearity, precision (mean and repeatability) and accuracy.


Assuntos
Metronidazol/química , Nistatina/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Antibacterianos/análise , Antifúngicos/análise , Calibragem , Análise dos Mínimos Quadrados , Metronidazol/isolamento & purificação , Análise Multivariada , Nistatina/isolamento & purificação , Análise de Regressão , Reprodutibilidade dos Testes
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...