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1.
J Med Chem ; 58(10): 4204-19, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25970039

RESUMO

Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure-activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of potent and LysoPS receptor subtype-selective agonists, particularly for P2Y10 and GPR174.


Assuntos
Lisofosfolipídeos/química , Receptores Acoplados a Proteínas G/agonistas , Receptores de Lisofosfolipídeos/agonistas , Receptores Purinérgicos P2/efeitos dos fármacos , Relação Estrutura-Atividade , Aminoácidos/química , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Glicerol/química , Células HEK293 , Humanos , Estrutura Molecular , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismo , Fator de Crescimento Transformador alfa/metabolismo
2.
Bioorg Med Chem ; 16(13): 6544-51, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18524599

RESUMO

We describe the synthesis and characterization of a series of water-soluble free-base, zinc, and copper porphyrin-oligonucleotide (ODN) conjugates. A non-charged tetraarylporphyrin was directly attached to the 5'-position of thymine via a short amide linker. Such a linker should allow for rigid connection to the adjacent nucleobases, thus increasing the sensitivity for monitoring conformational changes of the ODNs by electronic circular dichroism due to capping effects or ligand binding. Two complementary synthetic approaches have been used to incorporate porphyrin chromophores into the DNA. In the first approach a porphyrin carboxylic acid is conjugated to 5'-amino-ODN. In the second approach the phosphoramidite of the porphyrin-amido-thymidine is coupled to 5'-hydroxy-ODN using standard automated phosphoramidite chemistry. In both cases a spontaneous metallation of the free-base porphyrin in porphyrin-DNA conjugates was observed during the porphyrin-DNA conjugate cleavage from the solid support and its consequent deprotection using concentrated aqueous ammonia. Zinc and copper porphyrin-DNA conjugates were isolated by HPLC and characterized together with the anticipated free-base porphyrin-DNA conjugate. Authentic zinc and copper porphyrin-DNA conjugates were intentionally prepared from intentionally metallated porphyrins to compare their spectroscopic and HPLC characteristics with isolated metallospecies and to confirm the spontaneous metallation.


Assuntos
Cobre/química , Metaloporfirinas/química , Oligonucleotídeos/síntese química , Água/química , Zinco/química , Cromatografia Líquida de Alta Pressão , DNA/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oligonucleotídeos/química , Solubilidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria
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