Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chemistry ; : e202401719, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38995511

RESUMO

Monocarboxylate transporter 8 (MCT8) is a trans-membrane transporter, which mediates the cellular delivery of thyroid hormones, L-thyroxine (T4) and 3,5,3 '-triiodo-L-thyronine (T3). In humans, the MCT8 protein is encoded by the SLC16A2 gene and mutations in the transporter cause a genetic neurological disorder known as Allan-Herndon-Dudley syndrome (AHDS). MCT8 deficiency leads to impaired transport of thyroid hormones in the brain. Radiolabelled T4 and T3 or LC/MS-MS methods have been used to monitor the thyroid hormone uptake through MCT8. Herein, we developed a fluorescent based assay to monitor the thyroid hormone uptake through MCT8. A dansyl-based fluorescent probe having L-thyroxine moiety is found to be highly selective towards MCT8 in living cells. The high selectivity of the probe towards MCT8 can be attributed to the halogen bond-mediated recognition by the transporter protein. The presence of a free carboxylic acid group is essential for the specificity of the probe towards MCT8. Additionally, the selectivity of the probe for MCT8 is abolished upon esterification of the carboxylic group. Similarly, MCT8 does not recognize the probe when it contains a free amine group.

3.
Oncogene ; 40(44): 6248-6257, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34556811

RESUMO

The enzyme iodothyronine deiodinase type 3 (DIO3) contributes to cancer proliferation by inactivating the tumor-suppressive actions of thyroid hormone (T3). We recently established DIO3 involvement in the progression of high-grade serous ovarian cancer (HGSOC). Here we provide a link between high DIO3 expression and lower survival in patients, similar to common disease markers such as Ki67, PAX8, CA-125, and CCNE1. These observations suggest that DIO3 is a logical target for inhibition. Using a DIO3 mimic, we developed original DIO3 inhibitors that contain a core of dibromomaleic anhydride (DBRMD) as scaffold. Two compounds, PBENZ-DBRMD and ITYR-DBRMD, demonstrated attenuated cell counts, induction in apoptosis, and a reduction in cell proliferation in DIO3-positive HGSOC cells (OVCAR3 and KURAMOCHI), but not in DIO3-negative normal ovary cells (CHOK1) and OVCAR3 depleted for DIO3 or its substrate, T3. Potent tumor inhibition with a high safety profile was further established in HGSOC xenograft model, with no effect in DIO3-depleted tumors. The antitumor effects are mediated by downregulation in an array of pro-cancerous proteins, the majority of which known to be repressed by T3. To conclude, using small molecules that specifically target the DIO3 enzyme we present a new treatment paradigm for ovarian cancer and potentially other DIO3-dependent malignancies.


Assuntos
Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Iodeto Peroxidase/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cistadenocarcinoma Seroso/enzimologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Regulação para Baixo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Iodeto Peroxidase/antagonistas & inibidores , Iodeto Peroxidase/genética , Camundongos , Mimetismo Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Chemistry ; 25(48): 11180-11192, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31215686

RESUMO

The plasma membrane regulates the transport of molecules into the cell. Small hydrophobic molecules can diffuse directly across the lipid bilayer. However, larger molecules require specific transporters for their entry into the cell. Regulating the cellular entry of small molecules and proteins is a challenging task. The introduction of halogen, particularly iodine, to small molecules and proteins is emerging to be a promising strategy to improve the cellular uptake. Recent studies reveal that a simple substitution of hydrogen atom with iodine not only increases the cellular uptake, but also regulates the membrane transport. The strong halogen-bond-forming ability of iodine atoms plays a crucial role in the transport and the introduction of iodine may provide an efficient strategy for studying membrane activity and cellular functions and improving the delivery of therapeutic agents. This Concept article does not provide a comprehensive picture of membrane transport but highlights halogen-substitution as a novel strategy for understanding and regulating the cell-membrane traffic.


Assuntos
Membrana Celular/metabolismo , Iodo/metabolismo , Biocatálise , Transporte Biológico , Permeabilidade da Membrana Celular , Corantes Fluorescentes/metabolismo , Células HeLa , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Iodeto Peroxidase/metabolismo , Modelos Moleculares , Naftalimidas/metabolismo , Ligação Proteica , Conformação Proteica , Hormônios Tireóideos/metabolismo
5.
Angew Chem Int Ed Engl ; 58(24): 8156-8160, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31021048

RESUMO

Glutathione peroxidase (GPx) is a selenoenzyme that protects cells against oxidative damage. Although the formation of a seleninic acid (-SeO2 H) by this enzyme during oxidative stress has been proposed, a selenic acid has not been identified in cells. Herein, we report that the formation of a seleninic acid can be monitored in living cells by using a redox-active ebselen analogue with a naphthalimide fluorophore. The probe reacts with H2 O2 to generate the highly fluorescent seleninic acid. The electron withdrawing nature of the -SeO2 H moiety and strong Se⋅⋅⋅O interactions, which prevent the photoinduced electron transfer, are responsible for the fluorescence.


Assuntos
Ácidos Carboxílicos/química , Fluorescência , Glutationa Peroxidase/metabolismo , Compostos Organosselênicos/química
7.
Chemistry ; 25(13): 3391-3399, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605252

RESUMO

The poor uptake of fluorescent probes and therapeutics by mammalian cells is a major concern in biological applications ranging from fluorescence imaging to drug delivery in living cells. Although gaseous molecules such as oxygen and carbon dioxide, hydrophobic substances such as benzene, and small polar but uncharged molecules such as water and ethanol can cross the cell plasma membrane by simple passive diffusion, many synthetic as well as biological molecules require specific membrane transporters and channel proteins that control the traffic of these molecules into and out of the cell. This work reports that the introduction of halogen atoms into a series of fluorescent molecules remarkably enhances their cellular uptake, and that their transport can be increased to more than 95 % by introducing two iodine atoms at appropriate positions. The nature of the fluorophore does not play a major role in the cellular uptake when iodine atoms are present in the molecules, as compounds bearing naphthalimide, coumarin, BODIPY, and pyrene moieties show similar uptakes. Interestingly, the introduction of a maleimide-based fluorophore bearing two hydroxyethylthio moieties allows the molecules to cross the plasma and nuclear membranes, and the presence of iodine atoms further enhances the transport across both membranes. Overall, this study provides a general strategy for enhancing the uptake of organic molecules by mammalian cells.

8.
Angew Chem Int Ed Engl ; 57(29): 8989-8993, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-29846997

RESUMO

Small-molecule-based fluorescent probes have become important tools in biology for sensing and imaging applications. However, the biological applications of many of the fluorescent molecules are hampered by low cellular uptake and high toxicity. In this paper, we show for the first time that the introduction of halogen atoms enhances the cellular uptake of fluorescent molecules and the nature of halogen atoms plays a crucial role in the plasma membrane transport in mammalian cells. The remarkably higher uptake of iodinated compounds compared to that of their chloro or bromo analogues suggests that the strong halogen bonding ability of iodine atoms may play an important role in the membrane transport. This study provides a novel strategy for the transport of fluorescent molecules across the plasma membrane in living cells.


Assuntos
Corantes Fluorescentes/metabolismo , Halogênios/metabolismo , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Corantes Fluorescentes/análise , Halogênios/análise , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Microscopia Confocal , Modelos Moleculares
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...