[Search for antimetabolites among 5-trimethylsilyluracil nucleosides and their nonglycoside analogs].
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.
Mel'nik
S Ia
SIa
Bakhmedova
A A
AA
Iartseva
I V
IV
Preobrazhenskaia
M N
MN
Zaguliaeva
O A
OA
Mamaev
V P
VP
D000818:Animals; D000963:Antimetabolites; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D006027:Glycosides / Q000737:chemistry*; D007202:Indicators and Reagents; D007941:Leukemia P388; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects / Q000502:physiology; D014297:Trimethylsilyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D014498:Uracil / Q000737:chemistry* / Q000494:pharmacology; D014616:Vaccinia virus / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000963:Antimetabolites; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006027:Glycosides; D007202:Indicators and Reagents; D009705:Nucleosides; D014297:Trimethylsilyl Compounds; D014498:Uracil
Poisk antimetabolitov sredi nukleozidov 5-trimetilsililuratsila i ikh neglikozidnykh analogov.