Related Experiment Videos
Abstract:
Two routes for the synthesis of 6-substtituted 8-azaguanosine analogues are described. 2,5,6-Triamino-4(3H)-pyrimidinethione (1) was converted by methylation, nitrosation, and acetylation to -n-acetyl-7-(methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-amine (5). The reaction of 5 with 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride gave a mixture of the 7-, 8-, and 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-8-azapurines 4a-c which was converted to 8-azaguanosine (7c) and the corresponding 7- and 8-substituted isomers 7a and 7b. 4a-c were also converted with NaOMe to 6-O-methyl-8-azaguanosine (8c) and to the corresponding 7- and 8-substituted isomers 8a and 8b. The preferred route, however, to 6-substituted 8-azaguanosine analogues is an unambigous synthesis through N2-acetyl-6-(benzylthio)-N4-(2,3-O-isopropylidene-beta-D-ribofuranosyl)-5-nitro-2,4-pyrimidinediamine (13), prepared from the reaction of the chloropyrimidine 10 with the aminoribose 11. Catalytic hydrogenation of 13 gave the aminopyrimidine 14, which was converted with nitrous acid to the nucleoside beta-20. Treatment of beta-20 with dilute acid gave 7-(benzylthio)-3-beta-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-amine (19). Replacement of the benzylthio group of 19 with various nucleophilic reagents gave 8-aza-6-thioguanosine 17 and analogues 8c, 15, and 16. The thione 17 rearranges in aqueous solution to the thiasiazolopyrimidine 21. The parent [1,2,3]thiadiazolo[5,4-d]pyrimidine-5,7-diamine (24a) was prepared by nitrosation of the triaminopyrimidine (23a). Rearrangement of 24a in the presence of base gave a high yield of the thione 25a which could be rearranged with heat to 24a. Compounds 8a-c, 15-19, 24a, and 25 a were evaluated in the L1210 mouse leukemia screen- Only one compound, 8c, showed high cytotoxicity and borderline L1210 activity resulting from its en,ymatic conversion to 8-azaguanosine.