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1.
J Parkinsons Dis ; 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32716318

RESUMO

BACKGROUND: Synucleinopathy is a group of neurodegenerative disorders characterized by neurodegeneration and accumulation of alpha-synuclein (α-syn) aggregates in various brain regions. The detailed mechanism of α-syn-caused neurotoxicity remains obscure, which is partly due to the lack of a suitable model that retains the in vivo three-dimensional cellular network and allows a convenient dissection of the neurotoxic pathways. Recent studies revealed that the pre-formed recombinant α-syn amyloid fibrils (PFFs) induce a robust accumulation of pathogenic α-syn species in cultured cells and animals. OBJECTIVE: Our goal is to determine whether PFFs are able to induce the pathogenic α-syn accumulation and neurotoxicity in organotypic brain slice culture, an ex vivo system that retains the in vivo three-dimensional cell-cell connections. METHODS/RESULTS: Adding PFFs to cultured wild-type rat or mouse brain slices induced a time-dependent accumulation of pathogenic α-syn species, which was indicated by α-syn phosphorylated at serine 129 (pα-syn). The PFF-induced pα-syn was abolished in brain slices prepared from α-syn null mice, suggesting that the pα-syn is from the phosphorylation of endogenous α-syn. Human PFFs also induced pα-syn in brain slices prepared from mice expressing human α-syn on a mouse α-syn-null background. Furthermore, the synaptophysin immunoreactivity was inversely associated with pα-syn accumulation and an increase of neuronal loss was detected. CONCLUSION: PFF-treatment of brain slices is able to induce key pathological features of synucleinopathy: pα-syn accumulation and neurotoxicity. This model will be useful for investigating the neurotoxic mechanism and evaluating efficacy of therapeutic approaches.

2.
J Am Chem Soc ; 142(22): 10184-10197, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32368907

RESUMO

In addition to the already described ligand L4a, two pyclen-based lanthanide chelators, L4b and L4c, bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: [EuL4a], [SmL4a], [YbL4b], [TbL4c], and [DyL4c]. Additionally, the symmetrically arranged regioisomer L4a' was also synthesized as well as its [EuL4a'] complex to highlight the astonishing positive impact of the dissymmetrical N-distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition, in vivo two-photon microscopy was performed for the first time on a living zebrafish model with [EuL4a]. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.

3.
Chemphyschem ; 21(10): 1036-1043, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32176399

RESUMO

Cationic lanthanide complexes are generally able to spontaneously internalize into living cells. Following our previous works based on a diMe-cyclen framework, a second generation of cationic water-soluble lanthanide complexes based on a constrained cross-bridged cyclam macrocycle functionalized with donor-π-conjugated picolinate antennas was prepared with europium(III) and ytterbium(III). Their spectroscopic properties were thoroughly investigated in various solvents and rationalized with the help of DFT calculations. A significant improvement was observed in the case of the Eu3+ complex, while the Yb3+ analogue conserved photophysical properties in aqueous solvent. Two-photon (2P) microscopy imaging experiments on living T24 human cancer cells confirmed the spontaneous internalization of the probes and images with good signal-to-noise ratio were obtained in the classic NIR-to-visible configuration with the Eu3+ luminescent bioprobe and in the NIR-to-NIR with the Yb3+ one.

4.
J Inorg Biochem ; 205: 110978, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31951911

RESUMO

Based on our previous works involving two 1,4,7-triazacyclononane (tacn)-based ligands Hno2py1pa (1-Picolinic acid-4,7-bis(pyridin-2-ylmethyl)-1,4,7-triazacyclononane) and Hno1pa (1-Picolinic acid-1,4,7-triazacyclononane), we report here the synthesis of analogues bearing picolinate-based π-conjugated ILCT (Intra-Ligand Charge Transfer) transition antenna (HL1, HL2), using regiospecific N-functionalization of the tacn skeleton and their related transition metal complexes (e.g. Cu2+, Zn2+ and Mn2+). Coordination properties as well as their photophysical and electrochemical properties were investigated in order to quantify the impact of such antenna on the luminescent or relaxometric properties of the complexes. The spectroscopic properties of the targeted ligands and metal complexes have been studied using UV-Vis absorption and fluorescence spectrocopies. While the zinc complex formed with HL1 possesses a moderate quantum yield of 5%, complexation of Cu2+ led to an extinction of the luminescence putatively attributed to a photo-induced electron transfer, as supported by spectroscopic and electrochemical evidences. The [Mn(L2)]+ complex is characterized by a fluorescence quantum yield close to 8% in CH2Cl2. The potential interest of such systems as bimodal probes has been assessed from radiolabeling experiments conducted on HL1 and 64Cu2+ as well as confocal microscopy analyses and from relaxometric studies carried out on the cationic [Mn(L2)]+ complex. These results showed that HL1 can be used for radiolabeling, with a radiochemical conversion of 40% in 15 min at 100 °C. Finally, the relaxivity values obtained for [Mn(L2)]+, r1p = 4.80 mM-1·s-1 and r2p = 8.72 mM-1·s-1, make the Mn(II) complex an ideal candidate as a probe for Magnetic Resonance Imaging.

5.
Dalton Trans ; 48(44): 16476-16492, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31599913

RESUMO

Bispidones (3,7-diazabicyclo[3.3.1]nonan-9-one) are bicyclic analogues of the natural antiarrhythmic agent, spartein. They can straightforwardly be obtained from two successive Mannich reactions. Reduction of the ketone gives the corresponding bispidol. Substituted bispidones and bispidols offer a large playground by varying the substituents, the configuration of the carbon atoms in position 2 and 4 as well as the conformation of the bicycle. While chair-boat conformers display a strong affinity for κ-opioid receptors, chair-chair bispidines provide adaptable coordination spheres for transition metal and rare-earth ions. Because of their very rich coordination chemistry, substituted bispidines have emerged in various applications of coordination chemistry, such as catalysis, magnetism and medical imaging.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Complexos de Coordenação/química , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Animais , Complexos de Coordenação/metabolismo , Humanos , Metais Terras Raras/química , Conformação Molecular , Radioterapia/métodos , Elementos de Transição/química
6.
Inorg Chem ; 58(5): 3015-3025, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776218

RESUMO

The design, synthesis, and application of a nine-coordinate gadolinium(III)-containing spin label, [Gd.sTPATCN]-SL, for use in nanometer-distance measurement experiments by EPR spectroscopy is presented. The spin label links to cysteines via a short thioether tether and has a narrow central transition indicative of small zero-field splitting (ZFS). A protein homodimer, TRIM25cc, was selectively labeled with [Gd.sTPATCN]-SL (70%) and a nitroxide (30%) under mild conditions and measured using the double electron electron resonance (DEER) technique with both commercial Q-band and home-built W-band spectrometers. The label shows great promise for increasing the sensitivity of DEER measurements through both its favorable relaxation parameters and the large DEER modulation depth at both Q- and W-band for the inter-Gd(III) DEER measurement which, at 9%, is the largest recorded under these conditions.

8.
Chemistry ; 24(14): 3408-3412, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29341302

RESUMO

The design of original twisted charge transfer antennae in which a non-planar geometry is enforced thanks to one or two bulky ortho-Me substituents allows us to prepare the corresponding ultra-bright TbIII and DyIII bioprobes. The brightness of the TbIII derivative compares well with that of the benchmark Tb-Lumi4 complex. The first bio-imaging experiments with a DyIII luminescent bioprobe are also reported.

9.
Inorg Chem ; 56(19): 11738-11752, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28915014

RESUMO

Here we present the synthesis and characterization of a new bispidine (3,7-diazabicyclo[3.3.1]nonane) ligand with N-methanephosphonate substituents (L2). Its physicochemical properties in water, as well as those of the corresponding Cu(II) and Zn(II) complexes, have been evaluated by using UV-visible absorption spectroscopy, potentiometry, 1H and 31P NMR, and cyclic voltammetry. Radiolabeling experiments with 64CuII have been carried out, showing excellent radiolabeling properties. Quantitative complexation was achieved within 60 min under stoichiometric conditions, at room temperature and in the nanomolar concentration range. It was also demonstrated that the complexation occurred below pH 2. Properties have been compared to those of the analogue bispidol bearing a N-methanecarboxylate substituent (L1). Although both systems meet the required criteria to be used as new chelator for 64/67Cu in terms of the kinetics of formation, thermodynamic stability, selectivity for Cu(II), and kinetic inertness regarding redox- or acid-assisted decomplexation processes, substitution of the carboxylic acid function by the phosphonic moiety is responsible for a significant increase in the thermodynamic stability of the Cu(II) complex (+2 log units for pCu) and also leads to an increase in the radiochemical yields with 64CuII which is quantitative for L2.

10.
Chemistry ; 23(46): 10992-10996, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28759142

RESUMO

Responsive luminescent probes emitting in the near-infrared (NIR) are in high demand today for biological applications as they allow for the easy and unambiguous discrimination of autofluorescence. Due to their luminescence properties, lanthanide ions offer an interesting alternative to classical organic fluorescent dyes. This has stimulated the development of lanthanide-based responsive probes. Nevertheless, responsive probes that can operate in water with NIR-emitting lanthanide ions are scarce. In this communication, zinc fingers are shown to be versatile scaffolds to elaborate a variety of Zn2+ -responsive probes based on lanthanide emission and featuring desirable properties for the selective detection of Zn2+ in experimental conditions close to cellular. Of special interest is a NIR-emitting probe relying on Nd3+ emission.

11.
Org Biomol Chem ; 15(6): 1475-1483, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28116378

RESUMO

The first radiolabelling studies of a bispidine (3,7-diazabicyclo[3.3.1]nonane) derivative substituted by a glycinate pendant arm (L1) with 64Cu are reported. Labelling was fast and easily performed at room temperature and in a wide range of pH values. Under these conditions, radiochemical yields over 90% were achieved within 5 minutes at micromolar concentration of the ligand. A bifunctional analogue of L1 (L2) has been obtained by introducing an l-lysine amino acid on the bispidine skeleton. Ligand L2 demonstrates good radiolabelling capacities at room temperature and in water (pH 4 to pH 6). This new bispidine is a versatile platform which can easily react with NHS esters and can be subsequently coupled to a recognition unit in order to perform targeted Positron Emission Tomography (PET) imaging. As a proof of concept, two new bifunctional chelators (BFCs) with a biotin (L3) or a maleimide functional group (L4) have been synthesized. The biotinylated BFC is very valuable for pretargeting strategies using streptavidin-conjugated antibodies. The reactivity of the maleimide derivative L4 has been studied with the model peptide GP120. Quantitative coupling has been achieved under physiological conditions, showing a good regioselectivity towards cysteine residues versus lysine amino acids.

12.
Angew Chem Int Ed Engl ; 54(39): 11453-6, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26223738

RESUMO

A prototype luminescent turn-on probe for Cu(+) (and Ag(+)) is described, harnessing a selective binding site (log Kass = 9.4 and 7.3 for Cu(+) and Ag(+), respectively) based on the coordinating environment of the bacterial metallo-chaperone CusF, integrated with a terbium-ion-signaling moiety. Cation-π interactions were shown to enhance tryptophan triplet population, which subsequently sensitized, on the microsecond timescale, the long-lived terbium emission, offering a novel approach in bioinspired chemosensor design.


Assuntos
Cobre/análise , Elementos da Série dos Lantanídeos/química , Cátions , Dicroísmo Circular , Limite de Detecção , Luminescência , Análise Espectral/métodos
13.
Inorg Chem ; 54(9): 4431-44, 2015 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-25866934

RESUMO

A family of 2,4-pyridyl-disubstituted bispidol derivatives bearing methylene carboxylic acid ethyl esters (L1-L3), methylene carboxylic acids (L4 and L5), or methylenethiophene (L6) groups were synthesized. In water, all ligands form rigid 1:1 complexes in the presence of Zn(II) in which the bicycle adopts a chair-chair conformation (cis isomer), as observed by (1)H NMR and, in the case of ligand L1, by an X-ray diffraction crystal structure. Interestingly, addition of Zn(II) ions on ligand L1 induces a metal-mediated selective hydrolysis of the ethyl esters. This selective hydrolysis was not observed upon addition of other cations such as Na(+), Mg(+), and Ca(2+). Reduction of the central ketone was achieved to prevent ring opening via retro Diels-Alder reactions and to afford highly stable and water-soluble ligands (L4, L5, L6). The complexation properties of L4 and L6 were studied in solution, with a particular interest for ligand L4. Fast complexation occurs in strongly acidic media (pH = 1), with a high affinity toward Cu(II) (log KCuL4 = 19.2(3), pCu = 17.0 at pH 7.4, pCu = -log[Cufree], [Cu] = 1 × 10(-6) M, [L] = 1 × 10(-5) M) and high selectivity versus Co(II), Ni(II), and Zn(II), as shown by the values of the binding constants obtained from potentiometric and spectrophotometric titrations. Reversible redox potential with E1/2 = -430 mV (vs normal hydrogen electrode) was measured. The complex was found to be fairly inert from acid-assisted dissociation experiments in 5 M HClO4 (t1/2 = 110 d at 25 °C).


Assuntos
Ácidos Carboxílicos/química , Complexos de Coordenação/síntese química , Cobre/química , Tiofenos/química , Radioisótopos de Cobre , Cristalografia por Raios X , Reação de Cicloadição , Humanos , Cinética , Ligantes , Espectroscopia de Ressonância Magnética , Conformação Molecular , Medicina Nuclear/instrumentação , Medicina Nuclear/métodos , Potenciometria , Compostos Radiofarmacêuticos , Zinco/química
14.
Mol Cell Endocrinol ; 399: 201-7, 2015 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-25308967

RESUMO

A wide range of human sex hormone-binding globulin (hSHBG) affinity constants for testosterone (KA_hSHBG) has been reported in literature. To bring new insight on the KA_hSHBG value, we implemented a study of the molecular interactions occurring between testosterone and its plasma transport proteins by using surface plasmon resonance. The immobilization on the sensorchip of a testosterone derivative was performed by an oligoethylene glycol linker. For different plasmas with hSHBG concentrations, an assessment of the KA_hSHBG was obtained from a set of sensorgrams and curve-fitting these data. We observed that KA_hSHBG decreased, from at least two decades, when the plasma hSHBG concentration increased from 4.4 to 680 nmol/L. Our study shows a wide biological variability of KA_hSHBG that is related to the hSHBG concentration. These unexpected results may have a physiological significance and question the validity of current methods that are recommended for calculating free testosterone concentrations to evaluate androgen disorders in humans.


Assuntos
Globulina de Ligação a Hormônio Sexual/química , Ressonância de Plasmônio de Superfície/métodos , Testosterona/química , Humanos , Ligação Proteica , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue
15.
BMC Neurosci ; 14: 135, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-24192137

RESUMO

BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), α-synuclein (α-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against α-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human α-syn (hA30Pα-syn) and with two, one or no parkin knockout alleles. RESULTS: Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to α-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar α-syn species phosphorylated at S129 (PS129α-syn) were the predominant neuropathological feature in hA30Pα-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and α-syn truncated at D135 (α-synD135), indicating that PS129α-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. CONCLUSIONS: These findings suggest that Parkin deficiency acts as a protective modifier in α-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of α-syn deposits in end-stage disease.


Assuntos
Encéfalo/patologia , Degeneração Neural/genética , Ubiquitina-Proteína Ligases/genética , alfa-Sinucleína/genética , Animais , Western Blotting , Encéfalo/metabolismo , Modelos Animais de Doenças , Imunofluorescência , Humanos , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Destreza Motora , Degeneração Neural/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia
16.
Nanoscale ; 5(4): 1603-15, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23334308

RESUMO

Small Rigid Platforms (SRPs) are sub-5 nanometre gadolinium based nanoparticles that have been developed for multimodal imaging and theranostic applications. They are composed of a polysiloxane network surrounded by gadolinium chelates. A covalent coupling with quinoxaline derivatives has been performed. Such derivatives have proven their affinity for melanin frequently expressed in primary melanoma cases. Three different quinoxaline derivatives have been synthesised and coupled to the nanoparticles. The affinity of the grafted nanoparticles for melanin has then been shown in vitro by surface plasmon resonance on a homemade melanin grafted gold chip.


Assuntos
Gadolínio/química , Melaninas/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Ressonância de Plasmônio de Superfície/métodos , Sítios de Ligação , Teste de Materiais , Tamanho da Partícula
17.
J Org Chem ; 77(24): 11167-76, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23176106

RESUMO

Three new bispidone derivatives substituted by methylenecarboxylic ethyl ester groups have been synthesized in high yields as potential ligands for (64)Cu complexation and PET imaging. Their solution and solid-state structures have been determined by (1)H NMR spectroscopy and X-ray crystallography. These studies reveal a strong rigidity of the bicycle, which adopts either a chair-chair or a boat-chair conformation depending on the substituents in the N3 and N7 positions. A methyl substituent at N3 stabilizes the chair-chair conformation, whereas ethylacetate or 2-pyridylmethyl groups induce a considerable stabilization of the boat-chair conformation. However, when introduced in the position N7, a 2-pyridylmethyl substituent stabilizes the chair-chair isomer. The relative energies of the isomers and the isomerization process have been modeled by density functional theory calculations on a series of six N-substituted bispidones, including those newly synthesized. The subtle influence of the substituents has been related not only to the effect of steric hindrance on the thermodynamic stability but also to the presence of weak H-bonding interactions involving hydrogen-bonding acceptors, such as pyridylmethyl or ethylacetate substituents, and donors, such as C(sp2)-H of the pyridyl rings or C(sp3)-H at various positions of the bispidone skeleton.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ligantes , Modelos Moleculares , Conformação Molecular , Soluções , Estereoisomerismo , Especificidade por Substrato , Termodinâmica
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