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Search for antimetabolites among the nucleosides of 5-trimethylsilyl uracil and their non-glycoside analogues
S. Ya. Melnik, A. A. Bakhmedova, I. V. Yartseva, M. N. Preobrazhenskaya, O. A. Zagulyaeva, V. P. Mamaev
All-Union Cancer Research Centre, Academy of Medical Sciences of the USSR, Moscow, Institute of New Antibiotics, Academy of Medical Sciences of the USSR, Moscow; Novosibirsk Institute of Organic Chemistry, Siberian Division of the Academy of Sciences of the USSR, Novosibirsk
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-β-D-xylofurano-syl)-5-Tms-uracil. Under these conditions 1-(2,3-dideoxy-5-O-p-toluyl-α-D-glycero-pent-2-enofurariosyl)-5-Tms-uracil was obtained from 1-(2-deoxy-α-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'-amino-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 (mg/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.
Russian Journal of Bioorganic Chemistry 1991, 17 (11):1526-1533