ABSTRACT
The reaction of 2'-deoxy-5-trimethylsilyl(Tms)uridine with methanesulfonyl chloride led to the corresponding 3',5'-di-O-mesyl derivative, which was treated with lithium toluylate in DMF to give 2,3'-anhydro-1-(2-deoxy-5-O-p-toluyl-beta-D-xylofurano- syl)-5-Tms-uracil. Under these conditions 1-(2,3-dideoxy-5-O-p-toluyl-alpha-D- glycero-pent-2-enofuranosyl)-5-Tms-uracil was obtained from 1-(2-deoxy-alpha-D-ribofuranosyl)-5-Tms-uracil. Interaction of 2,3'-anhydronucleoside with LiN3 in DMF and successive deacylation with MeONa-MeOH gave 3'-azido-2',3'-dideoxy-5-Tms-uridine. Hydrogenation of this compound with 10% Pd/C in ethanol gave 3'-azido-2',3'-dideoxy-5-Tms-uridine. From 2,4,5-tris-Tms-uracil and 2,3-didehydrofurane in 1,2-dichloroethane in the presence of SnCl4 1-(2-tetrahydrofuranyl)-5-Tms-uracil was prepared. In a similar way 1-[(1,3-dioxy-2-propoxy)methyl]-5-Tms-uracil was synthesized by condensation of silylated uracil with 1,3-dibenzyloxy-2-acetoxymethylglycerol followed by the hydrogen transfer hydrogenolysis with cyclohexene--20% Pd(OH)2/C. None of the compounds exhibits cytotoxic activity against CaOv in vitro. The acycloderivative in concentration of 250 micrograms/ml has no effect on the HSV-1 and vaccinia virus replication in vitro. 3'-Azidonucleoside in dose of 100-750 mg/kg as well as 1-(2-tetrahydrofuranyl)-5-Tms-uracil in dose of 160-800 mg/kg were devoid of antitumour activity against P388 in vivo.
Subject(s)
Antimetabolites , Glycosides/chemistry , Nucleosides/chemistry , Trimethylsilyl Compounds/chemistry , Uracil/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Indicators and Reagents , Leukemia P388 , Nucleosides/pharmacology , Simplexvirus/drug effects , Simplexvirus/physiology , Trimethylsilyl Compounds/pharmacology , Uracil/pharmacology , Vaccinia virus/drug effects , Vaccinia virus/physiology , Virus Replication/drug effectsABSTRACT
In vivo experiments demonstrated antiherpetic activity of abnormal nucleoside, 5-trimethylsylil-2'-deoxyuridine alpha-anomer. In a model of herpetic encephalitis in cotton rats the preparation, inoculated intraperitoneally and administered orally, reduced the lethality by 25%-30% as compared with the controls, and also was effective in topical treatment of genital herpes in guinea pigs. Low toxicity, clear-cut antiherpetic activity, favourable metabolic properties as compared with known antiherpetic drugs indicate the necessity of further thorough investigation of this preparation.
