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1.
Chem Commun (Camb) ; 55(90): 13542-13545, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31647067
2.
Eur J Med Chem ; 179: 736-743, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284083

RESUMO

The formation of amyloid-ß (Aß) plaques in the brain is one of the main pathological features of Alzheimer's disease (AD). The imaging probes, capable of detecting Aß deposition, are important tools for early diagnosis of AD. In this article, we designed, synthesized and evaluated a cyanine-based near-infrared fluorescence (NIRF) probe ZT-1 for the detection of Aß deposits in the brain. The probe had excellent fluorescent properties with an emission maximum above 720 nm upon binding to Aß aggregates with affinity of 445.0 nM (Kd). Furthermore, ZT-1 exhibited good biostability, photostability, and binding selectivity toward Aß1-42 aggregates by in vitro fluorescence staining experiments. In vivo NIRF imaging result also revealed that our probe could efficiently differentiate transgenic and wild-type mice. All these studies indicated that ZT-1 is a promising fluorescent probe for Aß plaques in the AD brains.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Carbocianinas/química , Imagem Óptica , Placa Amiloide/química , Animais , Carbocianinas/síntese química , Relação Dose-Resposta a Droga , Raios Infravermelhos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Relação Estrutura-Atividade
3.
Org Biomol Chem ; 17(30): 7150-7154, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31317168

RESUMO

Free cysteine residues react with QuatCy 1, by simply mixing the protein and dye in aqueous buffer at 37 °C. Another dye, MHI-148, can be used for a similar labelling protocol, but QuatCy reacts faster with all proteins studied, except albumin; it emerges here that this is because MHI-148 instantly forms of a non-covalent complex with albumin, but QuatCy does not. Labelling with QuatCy has advantages insofar as it is over five times brighter, and much more photostable, than MHI-148, and combination labelling with this dye pair will allow multiplexing in the near-IR region.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Albumina Sérica Humana/química , Sítios de Ligação , Carbocianinas/síntese química , Corantes Fluorescentes/síntese química , Humanos , Raios Infravermelhos , Estrutura Molecular , Imagem Óptica
4.
Anal Chim Acta ; 1068: 60-69, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31072478

RESUMO

Three hydrogen sulfide (H2S) probes based on an azonia-cyanine skeleton were successfully designed and prepared. Probe 1a, containing 4-chloro-7-nitro-1,2,3-benzoxadiazole connected to the cyanine dye, had an emission at 660 nm that was enhanced 4.5-fold by the reduced photoinduced electron transfer process when reacting with H2S. Probes 1b and 1c were constructed from cyanine dyes with electron withdrawing 2,4-dinitrophenyl and 7-nitrobenzo[c] [1,2,5]oxadiazol-4-yl groups, respectively. Probes 1b and 1c gave off-on type responses with 169- and 17-fold fluorescent enhancements at 639 nm with H2S. Their emission properties were influenced by intramolecular hydrogen bonds and intramolecular charge transfer processes. The detection limits of probes 1a-1c were calculated at 178, 121, and 9.6 nM, respectively. The intracellular imaging experiments with HeLa cells indicated probe 1a was a mitochondria-targeting H2S probe, while probes 1b and 1c were lysosome-targeting H2S probes.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Imagem Óptica , Organelas/química , Carbocianinas/síntese química , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Estrutura Molecular , Células Tumorais Cultivadas
5.
Analyst ; 144(12): 3756-3764, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31070195

RESUMO

Protein phosphorylation is a very important regulatory mechanism in a majority of biological processes, and the determination of protein kinase activity plays a key role in the pathological study and drug development of kinase-related diseases. However, it is very challenging to in situ study endogenous protein kinase activity in a single living cell due to the shortage of in vivo efficient methods. Here, we propose a new strategy for direct determination of protein kinase activity in a single living cell by combining single molecule fluorescence correlation spectroscopy (FCS) with activity-based probes (ABPs). Ribosomal S6 kinase-2 (RSK2) was used as a model, and the ABPs were synthesized on the basis of RSK2 inhibitor FMK to specially label active RSK2 in living cells. Conventional FCS and MEMFCS (maximum entropy method) single molecule techniques were used to in situ determine RSK2 activity in living cells based on the difference in molecular weight between free probes and probe-RSK2 complexes. Furthermore, wild-type and mutated RSK2 were fused with enhanced green fluorescent protein (EGFP) using lentivirus infection, and fluorescence cross-correlation spectroscopy (FCCS) was used to verify the selective binding of ABPs to RSK2-EGFP fusion protein in living cells. Finally, FCS with ABPs was applied for in situ monitoring of the activation of endogenous RSK2 in the stimulation of serum, epidermal growth factor, kinase inhibitors and ultraviolet irradiation; we observed that endogenous RSK2 showed different behaviors in the cytoplasm and the nucleus in some stimulation. Our results document that FCS with ABPs is a very promising method for studying endogenous protein kinases in living cells.


Assuntos
Ensaios Enzimáticos/métodos , Proteínas Quinases S6 Ribossômicas 90-kDa/análise , Análise de Célula Única/métodos , Espectrometria de Fluorescência/métodos , Compostos de Boro/síntese química , Compostos de Boro/química , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Mutação , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Imagem Individual de Molécula/métodos
6.
Chemistry ; 25(34): 7998-8002, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-30947363

RESUMO

In this communication, the synthesis of three unknown polyfluorinated cyanine dyes and their application as selective markers for mitochondria are presented. By incorporating fluorous side chains into cyanine dyes, their remarkable photophysical properties were enhanced. To investigate their biological application, several different cell lines were incubated with the synthesized cyanine dyes. It was discovered that the presented dyes can be utilized for selective near-infrared-light (NIR) staining of mitochondria, with very low cytotoxicity determined by MTT assay. This is the first time that polyfluorinated cyanine fluorophores are presented as selective markers for mitochondria. Due to the versatile applications of polyfluorinated fluorophores in bioimaging and materials science, it is expected that the presented fluorophores will be stimulating for the scientific community.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Hidrocarbonetos Fluorados/química , Microscopia de Fluorescência/métodos , Mitocôndrias/ultraestrutura , Imagem Óptica/métodos , Células A549 , Carbocianinas/síntese química , Linhagem Celular , Corantes Fluorescentes/síntese química , Halogenação , Células HeLa , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrocarbonetos Fluorados/síntese química , Raios Infravermelhos , Microscopia Confocal/métodos
7.
Molecules ; 24(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974737

RESUMO

Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1⁻G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 µM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer.


Assuntos
Carbocianinas , Corantes Fluorescentes , Isoniazida , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase , Monoaminoxidase , Proteínas de Neoplasias , Neoplasias da Próstata , Carbocianinas/síntese química , Carbocianinas/química , Carbocianinas/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Isoniazida/química , Isoniazida/farmacologia , Masculino , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
8.
Chem Commun (Camb) ; 55(35): 5064-5067, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30896004
9.
Langmuir ; 35(5): 1440-1449, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30086625

RESUMO

Zwitterionic cross-linked biodegradable nanocapsules (NCs) were synthesized for cancer imaging. A polylactide (PLA)-based diblock copolymer with two blocks carrying acetylenyl and allyl groups respectively was synthesized by ring-opening polymerization (ROP). Azide-alkyne "click" reaction was conducted to conjugate sulfobetaine (SB) zwitterions and fluorescent dye Cy5.5 onto the acetylenyl-functionalized first block of the diblock copolymer. The resulting copolymer with a hydrophilic SB/Cy5.5-functionalized PLA block and a hydrophobic allyl-functionalized PLA block could stabilize miniemulsions because of its amphiphilic diblock structure. UV-induced thiol-ene "click" reaction between a dithiol cross-linker and the hydrophobic allyl-functionalized block of the copolymer at the peripheral region of nanoscopic oil nanodroplets in the miniemulsion generated cross-linked polymer NCs with zwitterionic outer shells. These NCs showed an average hydrodynamic diameter ( Dh) of 136 nm. They exhibited biodegradability, biocompatibility and high colloidal stability. In vitro study indicated that these NCs could be taken up by MIA PaCa-2 cancer cells. In vivo imaging study showed that, comparing to a small molecule dye, NCs had a longer circulation time, facilitating their accumulation at tumors for cancer imaging. Overall, this work demonstrates the applicability of zwitterionic biodegradable polymer-based materials in cancer diagnosis.


Assuntos
Nanocápsulas/química , Neoplasias/diagnóstico por imagem , Animais , Plásticos Biodegradáveis/síntese química , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/toxicidade , Carbocianinas/síntese química , Carbocianinas/química , Carbocianinas/toxicidade , Bovinos , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Humanos , Camundongos Nus , Nanocápsulas/toxicidade , Imagem Óptica/métodos , Poliésteres/síntese química , Poliésteres/química , Poliésteres/toxicidade
10.
Org Biomol Chem ; 16(41): 7579-7582, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30307458

RESUMO

Two 2'-deoxyuridines as new building blocks for automated DNA synthesis carry a small aryltetrazole as "photoclickable" group at their 5-positions. The postsynthetic "photoclick" labeling of such presynthesized DNA using a maleimide-modified Cy3 dye shows an up to 17-fold fluorogenicity due to an energy transfer between the pyrazoline moiety and the Cy3 fluorophore in the DNA products. This concept is also applicable to other maleimide-modified dyes.


Assuntos
Carbocianinas/química , DNA/análise , Desoxiuridina/análise , Corantes Fluorescentes/química , Maleimidas/química , Sequência de Bases , Carbocianinas/síntese química , Reação de Cicloadição , DNA/síntese química , Desoxiuridina/síntese química , Corantes Fluorescentes/síntese química , Maleimidas/síntese química , Processos Fotoquímicos , Coloração e Rotulagem
11.
Anal Chem ; 90(15): 8732-8735, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30027744

RESUMO

Legumain is one of the cysteine proteases which can serve as an essential indicator for cancer diagnosis. Near-infrared (NIR) nanoprobes with fluorescence "Turn On" property are advantageous in cancer diagnosis. However, to the best of our knowledge, using a completely organic NIR nanoprobe to image legumain activity either in vitro or in vivo has not been reported. Herein, employing a CBT-Cys click condensation reaction, we used a rationally designed NIR probe Cys(StBu)-Ala-Ala-Asn-Lys(Cy5.5)-CBT (1) to synthesize its nanoprobes 1-NPs with self-quenched fluorescence. Cell and animal experiments indicated that our nanoprobes were able to specifically image legumain activity in living cells and tumors with a NIR fluorescence "Turn On" manner. We envision that the nanoprobes could be applied for the diagnosis of legumain-related diseases in the near future.


Assuntos
Carbocianinas/química , Neoplasias do Colo/diagnóstico por imagem , Cisteína Endopeptidases/análise , Corantes Fluorescentes/química , Oligopeptídeos/química , Imagem Óptica/métodos , Animais , Carbocianinas/síntese química , Química Click , Neoplasias do Colo/enzimologia , Corantes Fluorescentes/síntese química , Células HCT116 , Humanos , Raios Infravermelhos , Camundongos , Microscopia de Fluorescência/métodos , Oligopeptídeos/síntese química
12.
Molecules ; 23(7)2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29933626

RESUMO

An efficient deep red (DR)-emitting organic solid based on a dicyano-phenylenevinylene derivative was reported. The structural and spectroscopic properties of the solid have been described in terms of crystallographic data and time-dependent DFT analysis. A noteworthy fluorescence quantum yield of 53% was observed for the brightest emitter cast into solid films. This result can be explained in terms of the aggregation-induced emission (AIE) effect.


Assuntos
Carbocianinas/síntese química , Corantes Fluorescentes/síntese química , Polivinil/química , Cristalografia por Raios X , Raios Infravermelhos , Estrutura Molecular , Teoria Quântica , Espectrometria de Fluorescência
14.
Chem Commun (Camb) ; 54(49): 6252-6255, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29736504

RESUMO

Fluorescent unimolecular micelles (FUMs) with multicolor emission acting as fluorescent nanoagents for optical fluorescence imaging have, for the first time, been reported. The FUMs show good water-solubility, ultra-small size, and enhanced biocompatibility, which endow the FUMs with versatile applications including organelle labeling, multicolor markers and high tumor accumulation, revealing that our design can serve as a rational strategy for the development of UM-based fluorescent nanoagents for bioprocess monitoring.


Assuntos
Corantes Fluorescentes/metabolismo , Metacrilatos/metabolismo , Micelas , Neoplasias/diagnóstico por imagem , Polietilenoglicóis/metabolismo , beta-Ciclodextrinas/metabolismo , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Carbocianinas/síntese química , Carbocianinas/química , Carbocianinas/metabolismo , Linhagem Celular Tumoral , Citoesqueleto/metabolismo , Feminino , Fluoresceínas/síntese química , Fluoresceínas/química , Fluoresceínas/metabolismo , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Lisossomos/metabolismo , Metacrilatos/síntese química , Metacrilatos/química , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Tamanho da Partícula , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Rodaminas/síntese química , Rodaminas/química , Rodaminas/metabolismo , Solubilidade , beta-Ciclodextrinas/síntese química , beta-Ciclodextrinas/química
15.
Bioorg Med Chem Lett ; 28(10): 1747-1752, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29673982

RESUMO

Successfully, one step two component synthesis of dimethine cyanine dyes, bis-dimethine cyanine dyes and icosamethine cyanine dyes 2-10via reaction of pyridinium salt 1 with some different aldehydes hope to obtain these compounds with enhanced biological potency as antitumor agents against spontaneous liver (HepG2), cervical (Hela), breast (MCF-7), pancreas (MIA), kidney (SN12C) and lung (H358). The impact of substituted drugs on the tumor cells was reflected by means of structure activity relationship (SAR). Among these dyes, icosamethine cyanine dye 8 recorded an excellent activity toward all the tested cell lines. The newly destined drugs were identified and emphasized by spectroscopy and elemental analyses.


Assuntos
Alcenos/farmacologia , Antineoplásicos/farmacologia , Carbocianinas/farmacologia , Corantes Fluorescentes/farmacologia , Alcenos/síntese química , Alcenos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Carbocianinas/síntese química , Carbocianinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
16.
Org Biomol Chem ; 16(18): 3382-3388, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29670968

RESUMO

A series of benzothiazolium-based hemicyanines (3a-3f) have been synthesized. Evaluation of their photophysical properties shows that they exhibit improved photophysical characteristics. In comparison with the available commercial MitoTrackers, the new probes revealed an enhanced Stokes shift (Δλ ∼ 80 nm) and minimized aggregation for increased sensitivity. The synthesized probes are found to exhibit excellent selectivity for mitochondrial staining in an oligodendrocyte cell line. Probes show almost no fluorescence in aqueous environments, while the fluorescence is increased by ∼10-fold in organic solvents, making it possible for mitochondrial imaging without the need for post-staining washing. Since the absorption peaks of probes are close to the laser wavelengths of 561 and 640 nm on a commercial confocal microscope, e.g.3a exhibits λabs ∼ 620 nm and λem ∼ 702 nm, they could be useful probes for mitochondrial tracking in live cells.


Assuntos
Benzotiazóis/química , Carbocianinas/química , Corantes Fluorescentes/química , Mitocôndrias/ultraestrutura , Oligodendroglia/ultraestrutura , Imagem Óptica/métodos , Benzotiazóis/síntese química , Carbocianinas/síntese química , Linhagem Celular , Fluorescência , Corantes Fluorescentes/síntese química , Humanos , Raios Infravermelhos , Microscopia Confocal/métodos
17.
Methods Appl Fluoresc ; 6(3): 034002, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29570093

RESUMO

Cyanine dyes are widely used in biological labeling and imaging because of their narrow near infrared emission, good brightness and high flexibility in functionalization, which not only enables multiplex analysis and multi-color imaging, but also greatly reduces autofluorescence from biological matter and increases signal-to-noise ratio. Unfortunately, their poor chemical- and photo-stability strongly limits their applications. The incorporation of cyanine dyes in silica nanoparticles provides a solution to the problem. On one hand, the incorporation of cyanine dyes in silica matrix can enhance their chemical- and photo-stability and increase brightness of the nanomaterials. On the other hand, silica matrix provides an optimized condition to host the dye, which helps to maintain their fluorescent properties during application. In addition, the well-established silane technique provides numerous functionalities for diverse applications. However, commercially available cyanine dyes are not very stable at high alkaline conditions, which will gradually lose their fluorescence over time. Our results showed that cyanine dyes are very vulnerable in the reverse micelle system, in which they will lose their fluorescence in less than half an hour. The existence of surfactant could greatly promote degradation of cyanine dyes. Fluorescent silica nanoparticles cannot be obtained at the high alkaline condition with the existence of surfactant. In contrast, the cyanine dyes are relatively stable in Stöber media. Owing to the fast formation of silica particles in Stöber media, the exposure time of cyanine dye in alkaline solution was greatly reduced, and highly fluorescent particles with good morphology and size distribution could be obtained via Stöber approach. However, the increasing water content in the Stöber could reduce the stability of cyanine dyes, which should be avoided. This research here provides a clear guidance on how to successfully synthesize cyanine dye-doped silica nanoparticles with good morphology, size distribution, stability and brightness.


Assuntos
Carbocianinas/química , Carbocianinas/síntese química , Nanopartículas/química , Dióxido de Silício/química , Humanos
18.
Bioconjug Chem ; 29(4): 1406-1418, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29493223

RESUMO

In this paper, we present three ratiometric near-infrared fluorescent probes (A-C) for accurate, ratiometric detection of intracellular pH changes in live cells. Probe A consists of a tetraphenylethene (TPE) donor and near-infrared hemicyanine acceptor in a through-bond energy transfer (TBET) strategy, while probes B and C are composed of TPE and hemicyanine moieties through single and double sp2 carbon-carbon bond connections in a π-conjugation modulation strategy. The specific targeting of the probes to lysosomes in live cells was achieved by introducing morpholine residues to the hemicyanine moieties to form closed spirolactam ring structures. Probe A shows aggregation-induced emission (AIE) property at neutral or basic pH, while probes B and C lack AIE properties. At basic or neutral pH, the probes only show fluorescence of TPE moieties with closed spirolactam forms of hemicyanine moieties, and effectively avoid blind fluorescence imaging spots, an issue which typical intensity-based pH fluorescent probes encounter. Three probes show ratiometric fluorescence responses to pH changes from 7.0 to 3.0 with TPE fluorescence decreases and hemicyanine fluorescence increases, because acidic pH makes the spirolactam rings open to enhance π-conjugation of hemicyanine moieties. However, probe A shows much more sensitive ratiometric fluorescence responses to pH changes from 7.0 to 3.0 with remarkable ratio increase of TPE fluorescence to hemicyanine fluorescence up to 238-fold than probes B and C because of its high efficiency of energy transfer from TPE donor to the hemicyanine acceptor in the TBET strategy. The probe offers dual Stokes shifts with a large pseudo-Stokes shift of 361 nm and well-defined dual emissions, and allows for colocalization of the imaging readouts of visible and near-infrared fluorescence channels to achieve more precisely double-checked ratiometric fluorescence imaging. These platforms could be employed to develop a variety of novel ratiometric fluorescent probes for accurate detection of different analytes in applications of chemical and biological sensing, imaging, and diagnostics by introducing appropriate sensing ligands to hemicyanine moieties to form on-off spirolactam switches.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Carbocianinas/síntese química , Citoplasma/química , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Imagem Óptica , Espectrometria de Fluorescência
19.
Bioorg Med Chem Lett ; 28(4): 572-576, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29402740

RESUMO

Prostate-specific membrane antigen (PSMA) is an important biological target for therapy and diagnosis of prostate cancer. In this study, novel multivalent PSMA inhibitors with glutamate-urea-lysine structures were designed to improve inhibition characteristics. Precursors of the novel inhibitors were prepared from glutamic acid with di-tert-butyl ester. A near-infrared molecular dye, sulfo-Cy5.5, was introduced into the precursors to generate the final PSMA fluorescent inhibitors, compounds 12-14, to visualize prostate cancer. Biological behaviors of the inhibitors were evaluated using in vitro inhibition assays, in vivo fluorescent imaging, and ex vivo biodistribution assays. Ki values from inhibition studies indicated that dimeric inhibitor 13 with a glutamine linker showed approximately 3-fold more inhibitory activity than monomeric inhibitor 12. According to other biological studies using a mouse model of prostate cancer, dimeric inhibitor compounds 13 and 14 had higher tumor accumulation than the monomer. However, glutamine-based dimeric inhibitor 13 showed lower liver uptake than dimeric inhibitor 14, which had a benzene structure. Thus, these studies suggest that glutamine-based dimeric inhibitor 13 can be a promising optical inhibitor of prostate cancer.


Assuntos
Antineoplásicos/farmacologia , Corantes Fluorescentes/farmacologia , Glutamato Carboxipeptidase II/antagonistas & inibidores , Glicoproteínas de Membrana/antagonistas & inibidores , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Carbocianinas/síntese química , Carbocianinas/metabolismo , Carbocianinas/farmacologia , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Distribuição Tecidual
20.
Chembiochem ; 19(12): 1250-1254, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29479781

RESUMO

Light-activated ("caged") antisense oligonucleotides are powerful molecules for regulating gene expression at submicron spatial resolution through the focal modulation of endogenous cellular processes. Cyclized caged oligos are particularly promising structures because of their inherent stability and similarity to naturally occurring circular DNA and RNA molecules. Here, we introduce an efficient route for cyclizing an antisense oligodeoxynucleotide incorporating a photocleavable linker. Oligo cyclization was achieved for several sequences in nearly quantitative yields through intramolecular copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Caging stability and light activation were characterized by FRET efficiency, denaturing gel assay, and melting temperature measurements. Finally, a cyclized caged oligo was designed to target gfap, and it gave a tenfold reduction in glial fibrillary acidic protein upon photoactivation in astrocytes.


Assuntos
Química Click/métodos , Oligonucleotídeos Antissenso/síntese química , Optogenética/métodos , Alquinos/síntese química , Alquinos/química , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Azidas/síntese química , Azidas/química , Sequência de Bases , Carbocianinas/síntese química , Carbocianinas/química , Catálise , Cobre/química , Ciclização , Reação de Cicloadição/métodos , Expressão Gênica/efeitos da radiação , Proteína Glial Fibrilar Ácida/genética , Humanos , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/genética
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