RESUMO
Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5'-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study the amino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding alpha-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.
Assuntos
Fármacos Anti-HIV/farmacologia , Esterases/metabolismo , Compostos Organofosforados/química , Estavudina/análogos & derivados , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Linhagem Celular , HIV-1/efeitos dos fármacos , Humanos , Hidrólise , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estavudina/metabolismo , Estavudina/farmacologia , SuínosRESUMO
A number of symmetric and asymmetric 5'-phosphate esters of the potent anti-varicella-zoster virus (VZV) agent 1-(beta-D-arabinofuranosyl)-5-prop-1-ynyluracil (882C; netivudine) were prepared as potential lipophilic, membrane-soluble prodrugs of the bio-active phosphate forms. The compounds were prepared by the base-catalysed coupling of various phosphorochloridates with the free nucleoside analogue. Compounds were fully characterized by a range of spectroscopic and analytical methods and were studied for their inhibition of several viruses in tissue culture. All of the phosphate esters were inactive against human cytomegalovirus, herpes simplex virus type 2, VZV, human immunodeficiency virus type 1 and influenza A virus (EC50 > 100 microM) except the 5'-(4-nitrophenyl phenyl) phosphate, which inhibited influenza A virus. The relative rate of esterase-mediated hydrolysis of one of the lead target structures was measured in order to rationalize the poor antiviral action, and data were collected on possible metabolites in support of this analysis. Cell-specific esterases are implicated as key determinants of the antiviral potency of prodrugs of this type.
Assuntos
Antivirais/síntese química , Arabinofuranosiluracila/análogos & derivados , Pró-Fármacos/síntese química , Animais , Antivirais/farmacologia , Antivirais/toxicidade , Arabinofuranosiluracila/síntese química , Arabinofuranosiluracila/farmacologia , Linhagem Celular , Esterases/metabolismo , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Fosfatos/síntese química , Fosfatos/farmacologia , Fosfatos/toxicidade , Pró-Fármacos/farmacologia , SuínosRESUMO
We report the design, synthesis and antiviral evaluation of a series of lipophilic, masked phosphoramidate derivatives of the anti-human immunodeficiency virus (HIV) nucleoside analogue d4T, designed to act as membrane-soluble prodrug forms for the free nucleotide. In particular, we report a series of 12 novel compounds with systematic variation in the structure of the carboxylate ester function. In order to rationalize the changes in antiviral action with variation of this moiety we applied our recently developed 31P NMR-based assay for carboxyesterase lability to this series. However, no clear positive correlation emerged, indicating that, at least within this series, factors other than simple esterase lability may be the major determinants of antiviral potency.