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1.
Chem Biol Interact ; 331: 109272, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33010220

RESUMO

A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference potassium channel opener cromakalim, on mitochondrial respiratory parameters and swelling, by comparing their effects with those of the parent compound cromakalim. For these three compounds, the oxygen consumption rate (OCR) was determined by high-resolution respirometry (HRR) and their impact on adenosine triphosphate (ATP) production and calcium-induced mitochondrial swelling was investigated. Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca-induced swelling. By contrast, the cromakalim analogue BPDZ490 (1) induced a strong increase of OCR, while the other benzopyran analogue BPDZ711 (2) caused a marked slowdown. For both compounds, 1 displayed a biphasic behavior while 2 still showed an inhibitory effect. Both compounds 1 and 2 were also found to decrease the ATP synthesis, with pronounced effect for 2, while cromakalim remained without effect. Overall, these results indicate that cromakalim, as parent molecule, does not induce per se any direct effect on mitochondrial respiratory function neither on whole cells nor on isolated mitochondria whereas both benzopyran analogues 1 and 2 display totally opposite behavior profiles, suggesting that compound 1, by increasing the maximal respiration capacity, might behave as a mild uncoupling agent and compound 2 is taken as an inhibitor of the mitochondrial electron-transfer chain.


Assuntos
Cromakalim/análogos & derivados , Mitocôndrias/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/farmacologia , Linhagem Celular , Cromakalim/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Canais de Potássio/agonistas , Canais de Potássio/metabolismo , Taxa Respiratória/efeitos dos fármacos
2.
J Med Chem ; 57(12): 5333-47, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24918261

RESUMO

In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.


Assuntos
1-Naftilamina/análogos & derivados , Acrilamidas/química , Anilidas/química , Cinamatos/química , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , 1-Naftilamina/síntese química , 1-Naftilamina/química , 1-Naftilamina/farmacologia , Acrilamidas/síntese química , Acrilamidas/farmacologia , Anilidas/síntese química , Anilidas/farmacologia , Animais , Cálcio/metabolismo , Cinamatos/síntese química , Cinamatos/farmacologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Dilatação Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Coelhos , Estereoisomerismo , Relação Estrutura-Atividade
3.
Front Cell Neurosci ; 8: 433, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25565966

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder in humans characterized by progressive degeneration of skeletal muscle and motor neurons in spinal cord, brainstem, and cerebral cortex causing skeletal muscle paralysis, respiratory insufficiency, and death. There are no cures or effective treatments for ALS. ALS can be inherited, but most cases are not associated with a family history of the disease. Mitochondria have been implicated in the pathogenesis but definitive proof of causal mechanisms is lacking. Identification of new clinically translatable disease mechanism-based molecular targets and small molecule drug candidates are needed for ALS patients. We tested the hypothesis in an animal model that drug modulation of the mitochondrial permeability transition pore (mPTP) is therapeutic in ALS. A prospective randomized placebo-controlled drug trial was done in a transgenic (tg) mouse model of ALS. We explored GNX-4728 as a therapeutic drug. GNX-4728 inhibits mPTP opening as evidenced by increased mitochondrial calcium retention capacity (CRC) both in vitro and in vivo. Chronic systemic treatment of G37R-human mutant superoxide dismutase-1 (hSOD1) tg mice with GNX-4728 resulted in major therapeutic benefits. GNX-4728 slowed disease progression and significantly improved motor function. The survival of ALS mice was increased significantly by GNX-4728 treatment as evidence by a nearly 2-fold extension of lifespan (360 days-750 days). GNX-4728 protected against motor neuron degeneration and mitochondrial degeneration, attenuated spinal cord inflammation, and preserved neuromuscular junction (NMJ) innervation in the diaphragm in ALS mice. This work demonstrates that a mPTP-acting drug has major disease-modifying efficacy in a preclinical mouse model of ALS and establishes mitochondrial calcium retention, and indirectly the mPTP, as targets for ALS drug development.

4.
Microvasc Res ; 83(2): 105-10, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22056402

RESUMO

We investigated the anti-angiogenic properties of GNX-686, a newly identified maleimide-based small molecule. In vitro studies on HUVEC showed that GNX-686 inhibited cell growth with an ED(50) of 20-25 µM, while human HeLa tumor cells and non-transformed embryonic mouse fibroblasts were less sensitive for the drug. More importantly, at 4 µM, a concentration that was non-toxic to any cell in culture, GNX-686 showed a significant inhibitory effect on tube formation by HUVEC, indicating a profound anti-angiogenic activity. Angiogenesis inhibition was subsequenly tested in the chorioallantoic membrane (CAM) of the chicken embryo. A significant angiostatic activity was observed in the CAM model, and results were compared with the effect of bevacizumab, a well known and clinically used VEGF inhibitor. Under our experimental conditions, GNX-686 was found to be as effective as bevacizumab, significantly changing the morphology of the vascular network, as illustrated and quantified by the relative number of branching points and the relative mean mesh size of the vascular network. In another in vivo model of neovascularization, the mouse retinopathy of prematurity (ROP), the vascular network of GNX-686-treated mice was significantly altered, reducing the density of the retinal microvasculature, as compared to the control retinas. Immunohistochemical processing of the GNX-686 treated (4µM) eyes showed over 50% reduction of the number of cell nuclei associated with neovasculature, as compared to the control-treated eye. Taken together these results demonstrate that GNX-686 is a promising anti-angiogenic compound that could be developed for the treatment of diseases characterized by aberrant angiogenesis such as ocular pathologies and cancer.


Assuntos
Inibidores da Angiogênese/farmacologia , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Maleimidas/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Retiniana/prevenção & controle , Retinopatia da Prematuridade/tratamento farmacológico , Animais , Animais Recém-Nascidos , Anticorpos Monoclonais Humanizados/farmacologia , Bevacizumab , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Retiniana/patologia , Neovascularização Retiniana/fisiopatologia , Retinopatia da Prematuridade/patologia , Retinopatia da Prematuridade/fisiopatologia
5.
Curr Biol ; 17(8): R280-3, 2007 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-17437704

RESUMO

Polo-like kinase 1 (Plk1) regulates mitotic progression in all eukaryotes and has been implicated in the transformation of human cells. Analysis of the cytological and anti-tumor activities of BI 2536, a novel, selective pharmacological inhibitor of Plk1, has connected chemistry and biology to the bedside.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Mitose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/farmacologia , Animais , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Humanos , Pteridinas/uso terapêutico , Quinase 1 Polo-Like
6.
Genomics Proteomics Bioinformatics ; 3(1): 58-60, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16144524

RESUMO

PoInTree (Polar and Interactive Tree) is an application that allows to build, visualize and customize phylogenetic trees in a polar interactive and highly flexible view. It takes as input a FASTA file or multiple alignment formats. Phylogenetic tree calculation is based on a sequence distance method and utilizes the Neighbor Joining (NJ) algorithm. It also allows displaying precalculated trees of the major protein families based on Pfam classification. In PoInTree, nodes can be dynamically opened and closed and distances between genes are graphically represented. Tree root can be centered on a selected leaf. Text search mechanism, color-coding and labeling display are integrated. The visualizer can be connected to an Oracle database containing information on sequences and other biological data, helping to guide their interpretation within a given protein family across multiple species. The application is written in Borland Delphi and based on VCL Teechart Pro 6 graphical component (Steema software).


Assuntos
Filogenia , Proteínas/classificação , Proteínas/genética , Alinhamento de Sequência/métodos , Análise de Sequência de DNA/métodos , Análise de Sequência de Proteína/métodos , Algoritmos , Bases de Dados de Proteínas , Evolução Molecular , Proteínas/química , Software
7.
Oncogene ; 24(13): 2218-28, 2005 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-15688026

RESUMO

Shc proteins participate in a variety of processes regulating cell proliferation, survival and apoptosis. The two ubiquitously expressed isoforms, p52Shc/p46Shc, couple tyrosine kinase receptors to Ras by recruiting Grb2/Sos complexes to a membrane-proximal localization. Tyrosine residues 239/240 and 317 become phosphorylated following receptor engagement and, as such, form two Grb2 binding sites, which have been proposed to be differentially coupled to Myc-dependent survival and to fos-dependent proliferation, respectively. Here, we have addressed the individual function of YY239/240 and Y317 in T-cell antigen receptor (TCR) signaling. We show that p52Shc is phosphorylated on both YY239/240 and Y317 following TCR engagement. Mutation of either YY239/240 or Y317 results in impaired interaction with Grb2 and inhibition of Ras/MAP kinase activation and CD69 induction, supporting a role for both Grb2 binding sites in this function. Substitution of either YY239/240 or Y317 also results in a defective activation of Rac and the coupled stress kinases JNK and p38. Furthermore, mutation of Y317 or, to a larger extent, of YY239/240, results in increased activation-induced cell death, which in cells expressing the FF239/240 mutant is accompanied by impaired TCR-dependent c-myc transcription. The data underline a pleiotropic and nonredundant role of Shc, mediated by both YY239/240 and Y317, in T-cell activation and survival.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sobrevivência Celular/fisiologia , Genes myc , Receptores de Antígenos de Linfócitos T/fisiologia , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Sítios de Ligação , Clonagem Molecular , Proteína Adaptadora GRB2 , Humanos , Células Jurkat , Microscopia Confocal , Mutagênese , Proteínas Recombinantes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Adaptadoras da Sinalização Shc , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Transfecção
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