RESUMO
Several new phorbol derivatives having ethereal substituents at the 12-position were synthesized and subjected to biological evaluation to find new candidates of an anti-HIV agent. Among them, 12-O-(methoxymethyl)phorbol 13-decanoate showed potent inhibitory activity against infection of HIV-1 in MT-4 cells (EC50: 1.3 ng/mL) and relatively low cytotoxicity (CC50: 8.3 microg/mL). This compound was also found to have sufficient stability in mouse plasma compared with the corresponding 12-acetate derivative, which was an equipotent HIV-1 inhibitor, but with an activity that decreased considerably after plasma treatment.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Forbóis/síntese química , Forbóis/farmacologia , Fármacos Anti-HIV/química , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Forbóis/químicaRESUMO
Several extracts from marine brown alga Sargassum micracanthum (Kuetzing) Endlicher were screened for their inhibitory activity on lipid peroxidation. In an in vitro study, methanol extract (Sm-M), chloroform/ methanol (3:1) extract and ethyl acetate fraction of Sm-M inhibited lipid peroxidation in rat liver homogenates. The IC(50) values were 0.70, 0.70 and 0.37 micro g/mL, respectively. These inhibitions were stronger than vitamin C and E. These extracts showed reductive activity on DPPH, the IC(50) values were 34, 37 and 11 micro g/mL, respectively. In an in vivo study, Sm-M had the effect on CCl4 induced liver injury in rats and Sm-M (120-1200 mg/kg, p.o.) lowered dose-dependently the level of lipid peroxidation in liver.
Assuntos
Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Phaeophyceae/química , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Relação Dose-Resposta a Droga , Hidrazinas/antagonistas & inibidores , Concentração Inibidora 50 , Fígado/metabolismo , Fígado/patologia , Masculino , Picratos , Ratos , Ratos Wistar , Vitamina E/farmacologiaRESUMO
Leukocyte common antigen-related molecule (LAR) is a receptor-like protein tyrosine phosphatase (PTPase) with two PTPase domains. In the present study, we detected the expression of LAR in the brain, kidney, and thymus of mice using anti-LAR PTPase domain subunit monoclonal antibody (mAb) YU1. In the thymus, LAR was expressed on CD4(-)CD8(-) and CD4(-)CD8(low) thymocytes. The development of thymocytes in CD45 knockout mice is blocked partially in the maturation of CD4(-)CD8(-) to CD4(+)CD8(+). We postulated that LAR regulates Lck and Fyn in the immature thymocytes. Transfection of wild-type LAR activated extracellular signal-regulated kinase signal transduction pathway in CD45-deficient Jurkat cells stimulated with anti-CD3 mAb. LAR mutants, with Cys to Ser mutation in the catalytic center of PTPase D1, bound to tyrosine-phosphorylated Lck and Fyn, and LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. The phosphorylated LAR was associated with Fyn Src homology 2 domain. Moreover, LAR dephosphorylated phosphorylated tyrosine residues in both the COOH terminus and kinase domain of Fyn in vitro. Our results indicate that Lck and Fyn would be substrates of LAR in immature thymocytes and that each LAR PTPase domain plays distinct functional roles in phosphorylation and dephosphorylation.