RESUMO
The 3'----5',3'----3' and 5'----5' dinucleoside monophosphates and methylphosphonates of 9-beta-D-arabinofuranosyladenine, as well as its 5'-(hydrogen phosphonate) and 5'-(methyl methylphosphonate) derivatives have been the subject of a systematic synthesis and examination of their biological, i.e. antiviral and cytostatic, properties. First the properly protected monomeric building blocks were prepared and then condensed to give fully protected intermediates. These latter were then deblocked to afford the unprotected compounds, which were fully characterized. Only the 3'----5' phosphodiester isomers 13 and 16 and, to a lesser extent, the 5'-(hydrogen phosphonate) derivative 21 showed marked biological activity.
Assuntos
Antivirais/síntese química , Arabinonucleotídeos/síntese química , Pró-Fármacos/síntese química , Fosfato de Vidarabina/síntese química , Animais , Linhagem Celular , Chlorocebus aethiops , Humanos , Isomerismo , Camundongos , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Fosfato de Vidarabina/farmacologiaRESUMO
Liver targeting of antiviral nucleoside analogs can be obtained by conjugating these drugs with the hepatotropic molecule lactosaminated serum albumin. We describe a new coupling procedure which uses the imidazolides of the phosphoric ester derivatives of the drugs in an alkaline medium. By this procedure conjugates are obtained with a high drug/carrier molar ratio and without the unwanted protein chemical changes produced by carbodiimides usually employed for this coupling.
Assuntos
Antivirais/síntese química , Imidazóis/síntese química , Nucleosídeos/síntese química , Albumina Sérica/síntese química , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Química Farmacêutica , Portadores de Fármacos , Estabilidade de Medicamentos , Eletroforese em Gel de Poliacrilamida , Ésteres/síntese química , Humanos , Concentração de Íons de Hidrogênio , Imidazóis/farmacocinética , Imidazóis/farmacologia , Ponto Isoelétrico , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Nucleosídeos/farmacocinética , Nucleosídeos/farmacologia , Ácidos Fosfóricos/síntese química , Fósforo , Ratos , Albumina Sérica/farmacologia , Fosfato de Vidarabina/síntese química , Fosfato de Vidarabina/farmacocinética , Fosfato de Vidarabina/farmacologiaRESUMO
A conjugate consisting of the antiviral nucleotide analogue adenine arabinoside 5'-monophosphate (araAMP, vidarabine monophosphate) and the naturally occurring polysaccharide arabinogalactan was synthesized. The conjugate consisted of 7.9 araAMP residues per molecule of arabinogalactan. The proposed structure of the conjugate was consistent with 13C NMR spectroscopic studies. Daily injections of the conjugate, at a dose of 3 mg of araAMP/kg, into woodchuck carriers of woodchuck hepatitis virus (WHV) decreased serum levels of WHV DNA. A dose of 3 mg/kg of unconjugated araAMP was ineffective, while a higher dose of araAMP (15 mg/kg, 14 days) produced a drop in WHV DNA. After cessation of dosing with the conjugate, serum viral DNA levels remained depressed for 42 days. In contrast, after cessation of dosing with araAMP, WHV DNA rapidly returned to original levels.