RESUMO
Synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils containing a vinyl (4a), 2-halovinyl (4b-d), or ethyl substituent at C-5 was achieved. These nucleosides were found to be about a log order less active than 2'-fluoro-5-iodo-ara-C (FIAC) against HSV-1, but they are much less cytotoxic against normal human lymphocytes than FIAC. Nucleosides 4a and 4e showed good activity against HSV-1 (ED50 = 0.16 and 0.24 microM, respectively) and HSV-2 (ED50 = 0.69 and 0.65 microM) with very little cytotoxicity (ID50 greater than 100 microM).
Assuntos
Antivirais/síntese química , Arabinofuranosiluracila/análogos & derivados , Simplexvirus/efeitos dos fármacos , Uridina/análogos & derivados , Animais , Arabinofuranosiluracila/síntese química , Arabinofuranosiluracila/uso terapêutico , Linhagem Celular , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Humanos , Indicadores e Reagentes , Rim , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
Syntheses of five pairs of cytosine and 5-fluorocytosinexylofuranosyl nucleosides in which the 3'-hydroxyl group is replaced by Cl, Br, OMs, or OTs are described. Those xylosyl nucleosides with a good leaving group at the 3' position exhibit good inhibitory activity against L5178Y and P815 mouse leukemic cells in vitro at rather low concentrations, and like that of ara-C this cytotoxicity is reversed by 2'-deoxycytidine but not by thymidine. Xylosylcytosines are not active against ara-C resistant lines of L5178Y and P815 cells; however, the corresponding 5-fluorocytosine analogues exhibit significant cytotoxicity against these ara-C resistant leukemic cell lines, and this activity is reversed by thmidine but not by deoxycytidine. These data support the "double-barreled" masked precursor hypothesis in that xylosyl-5-fluorocytosines substituted at the 3' position by a good leaving group exhibit activity akin to that of ara-C in the ara-C sensitive lines, while these nucleosides act as 5-fluoropyrimidines in the ara-C resistant lines.
Assuntos
Antineoplásicos/síntese química , Nucleotídeos de Citosina/síntese química , Animais , Linhagem Celular , Nucleotídeos de Citosina/metabolismo , Nucleotídeos de Citosina/farmacologia , Leucemia Experimental/tratamento farmacológico , Camundongos , Relação Estrutura-AtividadeRESUMO
A series of 5-substituted 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosines 7a-d and their corresponding uracils 9a-d,f were prepared by condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinosyl bromide (5) with appropriately trimethylsilylated pyrimidines followed by saponification of the protected nucleosides 6 or 8. 1-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (7e) was obtained by iodination of 7a. Iodination of 8a followed by removal of the protecting acyl-protecting groups afforded the 5-iodo nucleoside 9e. Several of these 2'-fluoro-substituted nucleosides completely obviated replication of herpes simplex virus type 1 (HSV-1) in monolayers of Vero cells at concentrations of 10-100 microgram/mL. The 5-iodocytosine analogue 7e was the most effective, showing 99.5% suppression of viral replication even at concentrations of 0.1 microgram/mL. The cytotoxicity of 7e to L5178Y or P815 cells in culture was minimal. A comparison of the efficacy of 7e against HSV-1 with other known nucleoside antiviral agents indicates that further in vitro and in vivo evaluation of 7e is warranted.
Assuntos
Antivirais/síntese química , Arabinonucleosídeos/síntese química , Nucleosídeos de Pirimidina/síntese química , Simplexvirus/efeitos dos fármacos , Arabinonucleosídeos/farmacologia , Nucleosídeos de Pirimidina/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A seven-step synthesis of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose, a versatile intermediate in the synthesis of chemotherapeutically important nucleosides, was achieved from 1,2:5,6-di-O-isopropylidene-3-O-tosyl-alpha-D-allofuranose. The crucial steps were the fluorination by use of potassium fluoride in acetamide and the conversion of 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose into 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D-arabinofuranose by periodate oxidation. Also described is the synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosine. This procedure affords good overall yields of products without formation of undesirable, isomeric intermediates and is suitable for large-scale preparations.
Assuntos
Arabinose/análogos & derivados , Desoxiaçúcares/síntese química , Cromatografia em Camada Fina , Cristalização , Citarabina/análogos & derivados , Flúor , Espectroscopia de Ressonância Magnética , Métodos , Rotação OcularRESUMO
Very recently, 1-N-methyl-psi-uridine was isolated from the culture filtrate of Streptomyces platensis var. clarensis along with an antibacterial and antiviral antibiotic, U-44590. We achieved chemical syntheses of 1-N-methyl-psi-uridine by selective methylation of psi-uridine in two different routes and established the identity of the synthetic nucleoside with the natural product.