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1.
ChemSusChem ; 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32672412

RESUMO

From electronic waste to Pd-catalyzed reaction! The straightforward valuation of palladium recovered from electronic waste is reported here. Following a classical leaching stage, palladium is selectively extracted from a complex aqueous mixture of metallic cations into an organic phase. Afterwards, the judicious choice of a surfactant enables stabilization of palladium during back extraction cycles, and the direct preparation of an aqueous micellar solution, which can be employed in a model Suzuki-Miyaura cross-coupling reaction. Clean phase separation is observed, and distribution of all components between organic and aqueous phases is mastered. The proposed process avoids several waste generating steps dedicated to palladium isolation and ultimate purification, as well as the preparation of palladium pre-catalyst. This novel approach enables a better use of both natural resources and industrial wastes, through new cycles in circular economy.

2.
J Mater Chem B ; 7(6): 927-939, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32255098

RESUMO

The purpose of this study was to develop micron-sized droplet emulsions able to increase the heat deposition of high intensity focused ultrasound (HIFU), aiming to accelerate the tumour ablation in highly perfused organs with reduced side effects. The investigated droplets consisted of a perfluorooctyl bromide (PFOB) core coated with a biocompatible fluorinated surfactant called F-TAC. The novelty of this work relies on the use, for this application, of a high boiling point perfluorocarbon core (142 °C), combined with an in-house fluorinated surfactant to formulate the emulsion, yielding quasi-reversible strong interactions between the HIFU beam and the droplets. In order to fine-tune the emulsion size, surfactants with different hydrophobic/hydrophilic ratios were screened. Different concentrations of PFOB droplets were homogeneously embedded in two different MRI compatible materials, exhibiting either ultrasound (US) absorbing or non-absorbing properties. For the US absorbing TMM, the speed of sound at each droplet concentration was also assessed. These TMM were sonicated by 1 MHz HIFU with acoustical power of 94 W at two different duty cycles. The temperature elevation was monitored accurately by MRI proton shift resonance frequency in near real-time. The presence of sono-sensitive droplets induced a significant increase of the HIFU thermal effect that persisted under repeated sonication of the same locus. Optimal enhancement was observed at the lowest concentration tested (0.1%) with an additional temperature rise at the focal point of approximately 4 °C per applied kJ of acoustic energy corresponding to one order of magnitude augmentation of the thermal dose. Furthermore, no deformation of the heating pattern pre- or post-focal was observed.


Assuntos
Fluorcarbonetos/química , Tensoativos/química , Materiais Biocompatíveis/química , Meios de Contraste/química , Ablação por Ultrassom Focalizado de Alta Intensidade/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Hipertermia Induzida , Imagem por Ressonância Magnética , Neoplasias/terapia , Tamanho da Partícula , Temperatura , Ultrassonografia
3.
J Magn Reson ; 295: 27-37, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30096550

RESUMO

OBJECTIVE: Perfluorocarbon nano- and micron-sized emulsions are a new field of investigation in cancer treatment due to their ability to be used as imaging contrast agents, or as delivery vectors for pharmaceuticals. They also demonstrated capability to enhance the efficiency of high intensity focused ultrasound thermo-therapy. In the context of new biomedical applications we investigated perfluorooctyl bromide (PFOB) theranostic droplets using 19F NMR. Each droplet contains biocompatible fluorinated surfactants composed of a polar Tris(hydroxymethyl)aminomethane head unit and hydrophobic perfluorinated tail (abbreviated as F-TAC). The influence of the droplet size on the oxygen loading capacity was determined from longitudinal relaxation (T1) data of 19F NMR signal. MATERIAL AND METHODS: Liquid PFOB and five samples of PFOB droplets of average diameter 0.177, 0.259, 1.43, 3.12 and 4.53 µm were tested with different oxygen levels. A dedicated gas exchange system was validated to maintain steady state oxygen concentrations, including a spatial gradient of oxygen concentration. A prototyped transmit-receive switchable 19F/1H quadrature coil was integrated on a 3 T clinical scanner. The coil is compatible with focused ultrasound sonication for future application. A spectroscopy FID inversion-recovery (IR) sequence was used to measure the T1 value per sample and per value of equilibrium oxygen pressure. Pixel wise, spatial T1 mapping was performed with magnetization prepared 2D gradient echo sequences in tissue mimicking gels doped with theranostic droplets. RESULTS: Experimental data indicated that the longitudinal relaxation rate of 19F signal of the investigated theranostic droplets depended approximately linearly on the oxygen level and its slope decreased with the particle size according to a second order polynomial over the investigated range. This semi-empirical model was derived from general thermodynamics and weak electrostatic forces theory and fitted the experimental data within 0.75% precision. The capacity of oxygen transportation for the described theranostic droplets tended to that of pure PFOB, while micron-sized droplets lost up to 50% of this capacity. In a specific setup producing a steady state gradient of oxygen concentration, we demonstrated spatial mapping of oxygen pressure gradient of 6 kPa/mm with 1 mm in-plane resolution. CONCLUSION: The size-tunable PFOB theranostic droplets stabilized with F-TAC surfactants could be characterized by 19F MRI in a clinical setup readily compatible with interventional in vivo studies under MR guidance. Current precision and spatial resolution of T1 mapping are promising. A potential challenge for further in vivo studies is the reduction of the imaging time.

4.
ACS Omega ; 3(1): 1014-1021, 2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31457945

RESUMO

Most therapeutic targets are proteins whose binding sites are hydrophobic cavities. For this reason, the majority of drugs under development are hydrophobic molecules exhibiting low solubility in water. To tackle this issue, a few percent of cosolvent, such as dimethyl sulfoxide (DMSO), is usually employed to increase drug solubility during the drug screening process. However, the few published studies dealing with the effect of adding DMSO showed that the affinity of hydrophobic ligands is systematically underestimated. To better understand the effect of DMSO, there is a need of studying its effect on a large range of systems. In this work, we used ß- and γ-cyclodextrins (made of 6 and 7 α-d-glucopyranoside units, respectively) as models of hydrophobic cavities to investigate the effect of the addition 5% DMSO on the affinity of 1-adamantane carboxylic acid (ADA) to these cyclodextrins. The two systems differ by the size of the cyclodextrin cavity. The evaluation of binding constants was performed using ultrasound velocimetry, nuclear magnetic resonance spectroscopy, and molecular simulations. All techniques show that the presence of 5% DMSO does not significantly modify the affinity of ADA for γ-cyclodextrin, while the affinity is dramatically reduced for ß-cyclodextrin. The bias induced by the presence of DMSO is thus more important when the ligand volume better fits the cyclodextrin cavity. Our work also suggests that free energy calculations provide a sound alternative to experimental techniques when dealing with poorly water-soluble drugs.

5.
Cent Nerv Syst Agents Med Chem ; 12(1): 7-14, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22280405

RESUMO

What is the origin of the complex vascular changes that exist in the CNS lesions of Multiple Sclerosis (MS)? From the beginning of the study of the pathological changes in MS in the 19th century, lesions were seen to be associated with veins. On a microscopic level, there have been numerous pathological changes to these vessels including altered structure and permeability, fibrinolysis, iron-related alterations and collagen deposition. Vascular changes in inflammatory conditions outside the CNS are well documented and we hypothesize that angiogenesis (the generation of new blood vessels from existing) is an integral process of lesion development and spread in MS. We demonstrated similar vascular abnormalities in MS and in the animal model, EAE. We measured the increase in angiogenesis-related genes in EAE and review herein the effectiveness of chemical inhibitors of angiogenesis (SU5416, thalidomide and several derivatives). We postulate that interference with angiogenesis provides a suitable non-immunological target for investigation in MS.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Inibidores da Angiogênese/química , Animais , Sistemas de Liberação de Medicamentos/tendências , Encefalomielite Autoimune Experimental/fisiopatologia , Humanos , Indóis/administração & dosagem , Indóis/química , Esclerose Múltipla/fisiopatologia , Pirróis/administração & dosagem , Pirróis/química , Talidomida/administração & dosagem , Talidomida/química
6.
ChemMedChem ; 5(12): 2057-64, 2010 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-20936622

RESUMO

The precise mechanism-of-action of thalidomide remains uncertain and might differ between diseases and under different clinical condition. With implications in the treatment of a variety of inflammatory and autoimmune diseases, as well as for use as an anticancer agent, alone or in combination with established therapeutics, it is clear that thalidomide and its derivatives deserve further scrutiny. In particular, thalidomide was shown to be effective in a mouse model of multiple sclerosis (MS), an autoimmune inflammatory disorder, called experimental autoimmune encephalomyelitis (EAE). Herein, we describe the synthesis and preliminary biological evaluation of new macromolecular prodrugs of thalidomide bearing an aminoalkyl group on the phthalimide ring. The effectiveness of these compounds to limit EAE was investigated, and it was shown that, at 100 mg kg⁻¹ thalidomide-equivalent dose, they abrogated the clinical and pathological features of EAE.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Talidomida/análogos & derivados , Administração Oral , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Talidomida/síntese química , Talidomida/uso terapêutico
7.
Bioorg Med Chem Lett ; 19(3): 878-81, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19103485

RESUMO

The present work deals with the synthesis of a new series of thalidomide derivatives for therapeutic applications. These compounds were evaluated in vitro on a human endothelial cell line EA.hy926 for their antiproliferative potential and in vivo on an experimental animal multiple sclerosis model called EAE as angiogenesis inhibitors. The preliminary results obtained on EAE assays seem to validate that anti-angiogenesis compounds could be promising tools for the treatment of MS.


Assuntos
Inibidores da Angiogênese/farmacologia , Química Farmacêutica/métodos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/farmacologia , Inibidores da Angiogênese/síntese química , Animais , Linhagem Celular , Proliferação de Células , Desenho de Fármacos , Células Endoteliais/metabolismo , Humanos , Modelos Químicos , Neovascularização Patológica , Talidomida/síntese química
8.
J Org Chem ; 73(14): 5602-5, 2008 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-18572921

RESUMO

A new family of glycodendrimer scaffolds containing 12 and 18 peripheral alpha-d-mannopyranosidic units has been synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloadditions using sulfurated dendritic scaffolds bearing alkyne functionalities and novel TRIS derivatives.


Assuntos
Dendrímeros/síntese química , Manosídeos/química , Trometamina/química , Acetilação , Dendrímeros/química , Glicosilação , Estrutura Molecular , Propano/química , Compostos de Sulfidrila/química
9.
Biophys J ; 94(11): 4348-57, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18310255

RESUMO

The principal difficulty in experimental exploration of the folding and stability of membrane proteins (MPs) is their aggregation outside of the native environment of the lipid bilayer. To circumvent this problem, we recently applied fluorinated nondetergent surfactants that act as chemical chaperones. The ideal chaperone surfactant would 1), maintain the MP in solution; 2), minimally perturb the MP's structure; 3), dissociate from the MP during membrane insertion; and 4), not partition into the lipid bilayer. Here, we compare how surfactants with hemifluorinated (HFTAC) and completely fluorinated (FTAC) hydrophobic chains of different length compare to this ideal. Using fluorescence correlation spectroscopy of dye-labeled FTAC and HFTAC, we demonstrate that neither type of surfactant will bind lipid vesicles. Thus, unlike detergents, fluorinated surfactants do not compromise vesicle integrity even at concentrations far in excess of their critical micelle concentration. We examined the interaction of surfactants with a model MP, DTT, using a variety of spectroscopic techniques. Site-selective labeling of DTT with fluorescent dyes indicates that the surfactants do not interact with DTT uniformly, instead concentrating in the most hydrophobic patches. Circular dichroism measurements suggest that the presence of surfactants does not alter the structure of DTT. However, the cooperativity of the thermal unfolding transition is reduced by the presence of surfactants, especially above the critical micelle concentration (a feature of regular detergents, too). The linear dependence of DTT's enthalpy of unfolding on the surfactant concentration is encouraging for future application of (H)FTACs to determine the stability of the membrane-competent conformations of other MPs. The observed reduction in the efficiency of Förster resonance energy transfer between donor-labeled (H)FTACs and acceptor-labeled DTT upon addition of lipid vesicles indicates that the protein sheds the layer of surfactant during its bilayer insertion. We discuss the advantages of fluorinated surfactants over other types of solubilizing agents, with a specific emphasis on their possible applications in thermodynamic measurements.


Assuntos
Toxina Diftérica/química , Transferência Ressonante de Energia de Fluorescência/métodos , Compostos de Flúor/química , Bicamadas Lipídicas/química , Chaperonas Moleculares/química , Fosfolipídeos/química , Mapeamento de Interação de Proteínas/métodos , Tensoativos/química , Sítios de Ligação , Ligação Proteica , Dobramento de Proteína
10.
Bioorg Med Chem Lett ; 16(5): 1111-4, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16386903

RESUMO

The synthesis of a new fluorocarbon amphiphilic drug carrier is described. A polyfunctional amino acid endowed with a fluorocarbon chain and a sugar moiety providing the amphiphilic character constitutes the central element of this structure. A (14)C-radiolabelled acetyl group was grafted onto the third function and the bioavailability of this molecule was specified in mice after IV administration. This amphiphilic drug carrier exhibits a rapid and homogeneous distribution to the whole tissues and slow elimination half-lives (higher than one day) through a biliary excretion without any toxicity (no measured DL 50 for concentrations up to 500 mg/kg).


Assuntos
Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Desenho de Fármacos , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Meia-Vida , Masculino , Camundongos , Estrutura Molecular , Nanoestruturas , Transplante de Neoplasias , Tensoativos/síntese química , Tensoativos/química , Tensoativos/farmacocinética
11.
Bioorg Med Chem Lett ; 14(2): 421-5, 2004 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-14698173

RESUMO

The synthesis of a tris(hydroxymethyl)acrylamidomethane (THAM)-derived cotelomer endowed with thalidomide units and a preliminary assessment of its biological activity are described. 4-Carboxy thalidomide and 4-(N-acryloyl) lysine thalidomide derivatives were prepared. The polymerization of these compounds with THAM in the presence of octanethiol as transfer reagent provided a water-soluble telomer bearing several thalidomide units. The ability of this telomer to inhibit angiogenesis in a mouse model of corneal neovascularization was compared to 4-carboxy thalidomide and thalidomide. A significant inhibition in area of neovascularization stimulated by a bFGF pellet was observed only in the mice treated with the telomer.


Assuntos
Inibidores da Angiogênese/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Talidomida/farmacologia , Trometamina/farmacologia , Alantoide/irrigação sanguínea , Alantoide/efeitos dos fármacos , Inibidores da Angiogênese/síntese química , Animais , Bovinos , Embrião de Galinha , Córion/irrigação sanguínea , Córion/efeitos dos fármacos , Córnea/irrigação sanguínea , Córnea/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , Talidomida/síntese química , Trometamina/síntese química
12.
Bioorg Med Chem Lett ; 12(7): 1067-70, 2002 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-11909719

RESUMO

Work reported herein deals with the synthesis and preliminary biological assessments of a new class of biocompatible telomeric carriers bearing peptidic RGDSK sequences as tumor cell targeting and tyrosine moieties labelled with 125I as in vivo probe. The radioactivity levels obtained in several tissues, after the intravenous injections of these telomers in mice bearing grafted B16 syngenic melanoma showed that the addition of a RGD residue to a telomeric structure confers it an increased affinity for the highly vascularized zone surrounding the tumor.


Assuntos
Materiais Biocompatíveis/química , Melanoma Experimental/diagnóstico por imagem , Oligopeptídeos/síntese química , Telômero/química , Acetilação , Animais , Materiais Biocompatíveis/farmacocinética , Portadores de Fármacos , Radioisótopos do Iodo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos/administração & dosagem , Cintilografia , Distribuição Tecidual
13.
Curr Med Chem Anticancer Agents ; 2(6): 645-65, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12678718

RESUMO

The last three decades have seen the development of new concepts in the biomedical and medical field based on the principle of drug carrying and in vivo pharmaco-targeting using synthetic carriers such as nanoparticles, liposomes or polymers. This review deals with the synthesis and biomedical applications of a new kind of macromolecular compounds: end-capped oligomers called telomers. The telomers, derived from Tris(hydroxymethyl)aminomethane bearing either a hydro- or a fluorocarbon tail, are described. Their functionality and biocompatibility enhance their potential in the biomedical and medical fields. Such compounds exhibit no cytotoxicity and are able to cross cell membranes by endocytosis. After i.v or per os administration in the animal, they exhibit a very good bio-availability and a homogeneous distribution in all tissues without any accumulation. Their ability to carry in vivo antimitotic drugs has been shown. Moreover, the grafting of different glycoside moieties onto the hydroxyl groups of telomers allows the selective targeting of specific receptors called integrins. Finally, we have shown the potential use of telomers bearing specific peptide ligands, such as RGD sequences, in the selective carrying of antimitotic drugs to the angiogenic zone surrounding tumors.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Polímeros/farmacocinética , Tensoativos/farmacocinética , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Portadores de Fármacos/farmacocinética , Humanos , Polímeros/química , Polímeros/uso terapêutico , Tensoativos/química , Tensoativos/uso terapêutico , Distribuição Tecidual , Trometamina/química , Trometamina/farmacocinética
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