RESUMEN
In order to evaluate their antiviral properties, a series of 4'-C-methyl-beta-D-ribofuranosyl purine and pyrimidine nucleosides has been prepared. Unfortunately, none of these 4'-branched nucleosides showed any antiviral activity or cytotoxcity when tested against HIV, HBV, and Yellow Fever virus.
Asunto(s)
Nucleósidos de Purina/síntesis química , Nucleósidos de Pirimidina/síntesis química , Antivirales/síntesis química , Diseño de Fármacos , Indicadores y Reactivos , Metilación , Nucleósidos de Purina/química , Nucleósidos de Pirimidina/química , RibosaRESUMEN
A suitably protected 4-C-hydroxymethyl-arabino-pentofuranose was prepared and condensed with the following nucleobases: uracil, 5-fluorouracil and thymine. The corresponding cytosine and 5-fluorocytosine derivatives have also been obtained respectively from the uracil and 5-fluorouracil nucleosides. Separation of the anomeric mixtures followed by deprotection afforded the target compounds that were found to be non-cytotoxic to CCRF-CEM leukemia cells.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Pentosas/síntesis química , Pentosas/farmacología , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacología , Fluorouracilo/análogos & derivados , Humanos , Leucemia/tratamiento farmacológico , Timina/análogos & derivados , Células Tumorales Cultivadas , Uracilo/análogos & derivadosRESUMEN
In the search for new chemotherapeutic agents, we have focused our work on the synthesis and the study of several unnatural beta-L-nucleoside analogues. In this paper, we report on the synthesis of beta-L-pentofuranonucleosides (and their 2'-deoxy derivatives) of 5-fluorouracil and their inhibitory effects on the proliferation of several murine and human tumor cells. The corresponding 5-fluorocytosine derivatives were also synthesized and their anti-HIV and anti-HBV activities have been evaluated.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Flucitosina/análogos & derivados , Fluorouracilo/análogos & derivados , Nucleósidos/síntesis química , Nucleósidos/farmacología , Animales , Fármacos Anti-VIH/farmacología , Antineoplásicos/química , Antineoplásicos/toxicidad , División Celular/efectos de los fármacos , Diseño de Fármacos , VIH/efectos de los fármacos , Humanos , Ratones , Nucleósidos/química , Nucleósidos/toxicidad , Estereoisomerismo , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células Tumorales CultivadasRESUMEN
The stereoselectivities of recombinant human deoxycytidine kinase (EC 2.7.1.74) (dCK) and of recombinant human cytidine deaminase (EC 3.5.4.5) (CDA) were investigated with respect to a series of cytidine analogs, most of them having the unnatural L-stereochemistry. The enantioselectivity of dCK was always low and generally favored the L-enantiomers in the case of beta-2',3'-dideoxycytidine (beta-ddC), 5-fluoro-beta-2',3'-dideoxycytidine (beta-FddC) and beta-cytidine (beta-riboC). Concerning beta-2'-deoxycytidine, dCK showed a preference for the D-enantiomer. All other examined beta-L-cytidine analogs, [1-beta-L-lyxofuranosyl cytosine (beta-L-lyxoC), l-beta-L-xylofuranosyl cytosine (beta-L-xyloC), and 5-fluoro-1-beta-L-xylofuranosyl cytosine (beta-L-Fxylo C)], were substrates of dCK regardless of the nature of the pentose. None of the studied alpha-L-anomers (alpha-L-riboC, alpha-L-araC, alpha-L-lyxoC, or alpha-L-xyloC) was a substrate of dCK. Contrasting with the relaxed enantioselectivity of dCK, CDA had a strict requirement for D-cytidine analogs since none of the already listed beta-L- or alpha-L analogs was a substrate or an inhibitor of the enzyme. The conjunction of the preceding stereochemical properties of dCK and CDA confers to L-cytidine analogs important potentialities in antiviral and anticancer therapies.
