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1.
Bioorg Med Chem Lett ; 30(6): 126983, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32019711

RESUMO

A synthetic strategy to access a novel family of nucleoside analogues bearing a C3'-nitrile substituted all-carbon quaternary center is presented herein. These purine bearing scaffolds were tested in two pancreatic cancer cell lines harboring either wild-type (BxPC3) or G12V KRAS (Capan2) mutations. A promising compound was shown to have significantly greater efficacy in the Capan2 cell line as compared to Gemcitabine, the clinical gold standard used to treat pancreatic cancer.


Assuntos
Antineoplásicos/química , Desoxicitidina/análogos & derivados , Nitrilas/química , Neoplasias Pancreáticas/tratamento farmacológico , Amidas/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzilaminas/química , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/química , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosilação , Humanos , Mutação , Ácidos Fosfóricos/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Purinas/química , Relação Estrutura-Atividade , Gencitabina
2.
J Org Chem ; 84(11): 7372-7387, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31088084

RESUMO

Reported herein is the synthesis of sialyl LewisX analogues bearing a trans-bicyclo[4.4.0] dioxadecane-modified 3- O,4- C-fused galactopyranoside scaffold that locks the carboxylate pharmacophore in either the axial or equatorial position. This novel series of bicyclic galactopyranosides are prepared through a stereocontrolled intramolecular cyclization reaction that has been evaluated both experimentally and by density functional theory calculations. The cyclization precursors are obtained from ß-d-galactose pentaacetate in a nine-step sequence featuring a highly diastereoselective equatorial alkynylation and Cu(I) catalyzed formation of the acetylenic α-ketoester moiety. Preliminary biological evaluations indicate improved activity as P-selectin antagonists for the axially configured analogues as compared to their equatorial counterparts.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Galactose/química , Antígeno Sialil Lewis X/química , Estrutura Molecular
3.
Mol Cell Biol ; 36(3): 507-21, 2016 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-26598607

RESUMO

In humans and in mice, mutations in the Ostm1 gene cause the most severe form of osteopetrosis, a major bone disease, and neuronal degeneration, both of which are associated with early death. To gain insight into Ostm1 function, we first investigated by sequence and biochemical analysis an immature 34-kDa type I transmembrane Ostm1 protein with a unique cytosolic tail. Mature Ostm1 is posttranslationally processed and highly N-glycosylated and has an apparent mass of ∼60 kDa. Analysis the subcellular localization of Ostm1 showed that it is within the endoplasmic reticulum, trans-Golgi network, and endosomes/lysosomes. By a wide protein screen under physiologic conditions, several novel cytosolic Ostm1 partners were identified and validated, for which a direct interaction with the kinesin 5B heavy chains was demonstrated. These results determined that Ostm1 is part of a cytosolic scaffolding multiprotein complex, imparting an adaptor function to Ostm1. Moreover, we uncovered a role for the Ostm1/KIF5B complex in intracellular trafficking and dispersion of cargos from the endoplasmic reticulum to late endosomal/lysosomal subcellular compartments. These Ostm1 molecular and cellular functions could elucidate all of the pathophysiologic mechanisms underlying the wide phenotypic spectrum of Ostm1-deficient mice.


Assuntos
Citosol/metabolismo , Cinesinas/metabolismo , Proteínas de Membrana/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Caenorhabditis elegans , Linhagem Celular , Chlorocebus aethiops , Citosol/química , Drosophila melanogaster , Células HEK293 , Humanos , Cinesinas/química , Proteínas de Membrana/química , Camundongos , Dados de Sequência Molecular , Processamento de Proteína Pós-Traducional , Transporte Proteico , Alinhamento de Sequência , Ubiquitina-Proteína Ligases/química , Peixe-Zebra
4.
J Biol Chem ; 286(2): 1508-16, 2011 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-21051538

RESUMO

Pressure and volume overload induce hypertrophic growth of postnatal cardiomyocytes and genetic reprogramming characterized by reactivation of a subset of fetal genes. Despite intense efforts, the nuclear effectors of cardiomyocyte hypertrophy remain incompletely defined. Endothelin-1 (ET-1) plays an important role in cardiomyocyte growth and is involved in mediating the neurohormonal effects of mechanical stress. Here, we show that the phenylephrine-induced complex-1 (PEX1), also known as zinc finger transcription factor ZFP260, is essential for cardiomyocyte response to ET-1 as evidenced in cardiomyocytes with PEX1 knockdown. We found that ET-1 enhances PEX1 transcriptional activity via a PKC-dependent pathway which phosphorylates the protein and further potentiates its synergy with GATA4. Consistent with a role for PEX1 in cardiomyocyte hypertrophy, overexpression of PEX1 is sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. Importantly, transgenic mice with inducible PEX1 expression in the adult heart develop cardiac hypertrophy with preserved heart function. Together, the results identify a novel nuclear effector of ET-1 signaling and suggest that PEX1 may be a regulator of the early stages of cardiac hypertrophy.


Assuntos
Cardiomegalia , Endotelina-1/metabolismo , Transdução de Sinais/fisiologia , Transativadores/genética , Transativadores/metabolismo , Fatores Etários , Animais , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Células Cultivadas , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/citologia , Fosforilação/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Ratos , Transfecção
5.
Proc Natl Acad Sci U S A ; 107(45): 19356-61, 2010 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-20974940

RESUMO

In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.


Assuntos
Septo Interatrial/citologia , Endocárdio/citologia , Fator de Transcrição GATA4/fisiologia , Cardiopatias/congênito , Óxido Nítrico Sintase Tipo III/fisiologia , Proteínas com Domínio T/fisiologia , Animais , Septo Interatrial/patologia , Sobrevivência Celular , Endocárdio/patologia , Haploinsuficiência , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/genética , Camundongos , Fenótipo , Proteínas com Domínio T/análise
6.
Clin Cancer Res ; 10(8): 2594-9, 2004 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15102660

RESUMO

PURPOSE: Treatment of head and neck cancer often associates different therapeutic modalities, including surgery, radiotherapy, and chemotherapy. In an attempt to optimize therapeutics, the identification of molecular markers linked to response to chemotherapy remains important. Recently, the involvement of metalloproteinases in resistance to chemotherapy was suggested through their interaction with the Fas/Fas ligand pathway. Indeed metalloproteinases enhance Fas ligand shedding modulating chemotherapy efficiency. On the basis of these findings, we tested the existence of a correlation between response to chemotherapy and four metalloproteinase polymorphisms in a prospective series of 148 head and neck cancer patients. EXPERIMENTAL DESIGN: Patients were genotyped using automated fragment analysis and 5'-nuclease allelic discrimination assay. Response to chemotherapy was clinically assessed without knowledge of the genotype status. RESULTS: A significant relation between the metalloproteinase type 3 (MMP3) -1612insA polymorphism and response to chemotherapy was identified. Indeed, patients with the 6A/6A genotype responded more frequently (86%) to treatment as compared with patients with the 5A/6A (65%) or 5A/5A (55%) genotypes (P = 0.04). A multivariate analysis, including tumor stage, gender, TP53 mutations, and MMP3 polymorphism, showed that the 6A/6A genotype was an independent factor of response to 5-fluorouracil-cisplatin chemotherapy in head and neck cancer patients with an odds ratio of 6.7 as compared with the 5A/5A genotype. CONCLUSIONS: This work showed that genotyping the MMP3 gene enhancer polymorphism -1612insA could help predict chemosensitivity in head and neck cancer patients.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metaloproteinase 3 da Matriz/genética , Polimorfismo Genético , Idoso , Alelos , Cisplatino/uso terapêutico , Proteína Ligante Fas , Feminino , Fluoruracila/uso terapêutico , Genes p53 , Genótipo , Humanos , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 7 da Matriz/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Razão de Chances , Prognóstico , Estudos Prospectivos , Fatores Sexuais , Resultado do Tratamento , Receptor fas/metabolismo
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