RESUMO
A series of dinucleoside 5-polyphosphates UpnU (n = 2-7) was synthesized. Their relative potencies as agonists at the G-protein-coupled receptors P2Y1, P2Y2, P2Y4, and P2Y6 were determined by intracellular calcium measurements using fluorescent imaging techniques. The correlation of phosphate chain length to activities at these receptors is discussed.
Assuntos
Fosfatos de Dinucleosídeos/metabolismo , Agonistas do Receptor Purinérgico P2 , Nucleotídeos de Uracila/metabolismo , Cálcio/metabolismo , Fosfatos de Dinucleosídeos/síntese química , Humanos , Ligação Proteica , Receptores Purinérgicos P2/metabolismo , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Transdução Genética , Células Tumorais Cultivadas , Nucleotídeos de Uracila/síntese químicaRESUMO
The P2 family of membrane-bound receptors is activated by naturally occurring nucleotides. When activated, these widely distributed receptors elicit cellular signaling which mediate multiple tissue-specific effects throughout the body. P2X receptors are ligand-gated ionotropic channels, while P2Y receptors belong to the superfamily of metabotropic G protein-coupled receptors. To date, there are six human cloned and functionally characterized subtypes of the P2Y family: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11 and P2Y12. There exists enough agonist specificity between receptor subtypes to allow functional identification of newly found putative receptors. There are few specific antagonists of the P2Y receptors.
Assuntos
Receptores Purinérgicos P2/efeitos dos fármacos , Animais , Ensaios Clínicos como Assunto , Síndromes do Olho Seco/tratamento farmacológico , Humanos , Imuno-Histoquímica , Ligantes , Agonistas do Receptor Purinérgico P2 , Antagonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2/metabolismo , Distribuição TecidualRESUMO
A series of 2-amino-9-(3-azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)-6- substituted-9H-purines was synthesized and tested for the ability to protect MT4 cells from the cytopathic effect of HIV-1IIIB. These compounds were prepared by a combination of chemical and enzymatic reactions. Some of the nucleoside analogs with 6-alkoxy, 6-alkylamino, or 6-arylamino substituents were active against HIV-1IIIB. Their IC50 values were in the range of 2-60 microM. In contrast, analogs with 6-thio, 6-alkylthio, 6-methyl, or 6-carbonitrile substituents did not protect cells from the cytopathic effect of HIV infection.
Assuntos
Antivirais/química , Antivirais/farmacologia , Didesoxinucleosídeos/química , HIV-1/efeitos dos fármacos , Zidovudina/análogos & derivados , Antivirais/síntese química , Linhagem Celular Transformada/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Guanosina/análogos & derivados , Guanosina/química , Humanos , Lactobacillus/enzimologia , Pentosiltransferases/metabolismo , Purinas/química , Purinas/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/virologia , Timidina/química , Timidina/metabolismo , Zidovudina/síntese química , Zidovudina/farmacologiaRESUMO
3'-Amino-2',3'-dideoxyribonucleosides of thymine, uracil, and 5-iodouracil (1-3) were synthesized from the corresponding 2'-deoxyribonucleosides via the threo-3'-chloro and the erythro-3'-azido derivatives. Corresponding aminonucleosides of 5-bromouracil, 5-chlorouracil, and 5-fluorouracil (4-6) were synthesized enzymatically with 3'-amino-2',3'-dideoxythymidine as the aminopentosyl donor and thymidine phosphorylase (EC 2.4.2.4) as the catalyst. 3'-Amino-2',3'-dideoxycytidine (7) was synthesized by amination of the 3'-azido precursor of 3'-amino-2',3'-dideoxyuridine. The biological activity of 3'-amino-2',3'-dideoxy-5-fluorouridine (6) was notable among this group of aminonucleosides. It had an ED50 of 10 microM against adenovirus and was not appreciably cytotoxic to mammalian cells in culture. It also had activity against some Gram-positive bacteria but not against a variety of Gram-negative bacteria. The other aminonucleosides (1-5 and 7) lacked or exhibited weak antiviral and antibacterial activities. The only compounds in this group that were appreciably toxic to mammalian cells in culture were the thymidine and deoxycytidine analogues (1 and 7).
Assuntos
Desoxirribonucleosídeos/farmacologia , Animais , Células da Medula Óssea , Divisão Celular/efeitos dos fármacos , Células do Tecido Conjuntivo , Desoxirribonucleosídeos/síntese química , Humanos , Camundongos , Testes de Sensibilidade MicrobianaAssuntos
Amidinas/farmacologia , Amidoidrolases/metabolismo , Endopeptidases/metabolismo , Compostos Heterocíclicos/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Benzamidinas/farmacologia , Fibrinolisina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Indóis/farmacologia , Peso Molecular , Ativadores de Plasminogênio/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/farmacologiaRESUMO
Several aromatic mono- and diamidines were found to block cell fusion induced by respiratory syncytial virus. The best inhibitors were able to achieve complete suppression of syncytium formation at a concentration of 1.0 microM. Inhibition occurred in respiratory syncytial virus-infected HEp-2 and CV-1 cells, but the same inhibitors were ineffective in preventing fusion induced by parainfluenza virus type 3. The fusion inhibitors did not reduce single-cycle virus yields, but did reduce multiple-cycle yields. In addition, the active compounds caused a significant retardation of respiratory syncytial virus penetration. The mechanism by which amidines interfere with respiratory syncytial virus-host cell interactions is unknown, but parallels can be drawn between antiviral activity and the ability of the compounds to inhibit certain trypsin-like proteases.
