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1.
ACS Med Chem Lett ; 9(7): 612-617, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034588

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC50 of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.

2.
Acad Radiol ; 20(9): 1069-73, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23931418

RESUMO

RATIONALE AND OBJECTIVES: This article addresses the medical and legal implications of disruptive physician behavior. In addition, this article will address the appropriate use of due process in peer review of disruptive physician behavior. CONCLUSIONS: While most hospitals and even national organizations, like the American Medical Association, have definitions for what constitutes disruptive physician behavior, these definitions have been further examined and clarified in court rulings. These court rulings not only further clarify what constitutes disruptive behavior but also establish a threshold for revocation/nonrenewal of a physician's hospital privileges.


Assuntos
Emprego/legislação & jurisprudência , Relações Interprofissionais , Inabilitação do Médico/legislação & jurisprudência , Médicos/legislação & jurisprudência , Má Conduta Profissional/legislação & jurisprudência , Radiologia/legislação & jurisprudência , Estados Unidos
4.
J Med Chem ; 52(14): 4400-18, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19522463

RESUMO

Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.


Assuntos
Descoberta de Drogas , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular , Humanos , Fígado/citologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Estereoisomerismo , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacocinética
5.
J Am Chem Soc ; 127(41): 14383-7, 2005 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-16218633

RESUMO

Herein we report a semisynthetic method of producing membrane-anchored proteins. Ligation of synthetic lipids with designed anchor structures to proteins was performed using native chemical ligation (NCL) of a C-terminal peptide thioester and an N-terminal cysteine lipid. This strategy mimics the natural glycosylphosphatidylinositol (GPI) linkage found in many natural membrane-associated proteins; however, the synthetic method utilizes simple lipid anchors without glycans. Synthetically lipidated recombinant green fluorescent protein (GFP) was shown to be stably anchored to the membrane, and its lateral fluidity was quantitatively characterized by direct fluorescence imaging in supported membranes. Circumventing the steps of purification from native cell membranes, this methodology facilitates the reconstitution of membrane-associated proteins.


Assuntos
Proteínas de Fluorescência Verde/síntese química , Bicamadas Lipídicas/síntese química , Lipídeos/química , Proteínas de Fluorescência Verde/química , Bicamadas Lipídicas/química , Estrutura Molecular
7.
Annu Rev Biochem ; 71: 593-634, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12045107

RESUMO

Protein glycosylation is widely recognized as a modulator of protein structure, localization, and cell-cell recognition in multicellular systems. Glycoproteins are typically expressed as mixtures of glycoforms, their oligosaccharides being generated by a template-independent biosynthetic process. Investigation of their function has been greatly assisted by sources of homogeneous material. This review summarizes current efforts to obtain homogeneous glycopeptide and glycoprotein materials by a variety of methods that draw from the techniques of recombinant expression, chemical synthesis, enzymatic transformation, and chemoselective ligation. Some of these techniques remove obstacles to glycoprotein synthesis by installing nonnative linkages and other modifications for facilitated assembly. The end purpose of the described approaches is the production of glycosylated materials for experiments relevant to the biological investigation of glycoproteins, although the strategies presented apply to other posttranslational modifications as well.


Assuntos
Glicopeptídeos/química , Glicopeptídeos/síntese química , Glicoproteínas/química , Glicoproteínas/síntese química , Sequência de Aminoácidos , Glicopeptídeos/metabolismo , Glicoproteínas/metabolismo , Glicosilação , Glicosilfosfatidilinositóis/metabolismo , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Mucinas/química , Selectina-P/metabolismo , Serina/química , Treonina/química
8.
Org Lett ; 4(8): 1359-61, 2002 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-11950362

RESUMO

Here we report a concise stereoselective synthesis of myo-inositol via ring-closing metathesis. A readily available bis-Weinreb amide of D-tartrate served as a key intermediate. [reaction: see text]


Assuntos
Glicosilfosfatidilinositóis/síntese química , Inositol/síntese química , Animais , Sequência de Carboidratos , Eritrócitos/enzimologia , Indicadores e Reagentes , Inositol/química , Estereoisomerismo , Trypanosoma brucei brucei/química
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