SYNTHESIS, ANTIPROLIFERATIVE AND ANTIVIRAL ACTIVITY OF IMIDAZO[4,5-D]ISOTHIAZOLE NUCLEOSIDES AS 5 5 FUSED ANALOGS OF NEBULARINE AND 6-METHYLPURINE RIBONUCLEOSIDE/

A series of imidazo[4,5-d]isothiazole nucleosides related to the antib iotic nebularine and the highly cytotoxic 6-methyl-9-beta-D-ribofurano sylpurine have been synthesized from the corresponding heterocycles. T he sodium salt glycosylation of the imidazo[4,5-d]isothiazoles proceed ed smoothly, giving mixtures of N-4 and N-6 regioisomers in generally good yields. The protected derivatives were deblocked using standard c onditions to afford the desired imidazo[4,5-d]isothiazole nucleosides, usually as crystalline solids. None of the new nucleosides or heteroc ycles displayed selective activity against human cytomegalovirus (HCMV ) or herpes simplex virus type 1 (HSV-1). The N-6 glycosylated imidazo [4,5-d]isothiazoles were completely inactive up to the highest concent ration tested. The N-6 glycosylated imidazo[4,5-d]isothiazoles also we re inactive in antiproliferative and cytotoxicity assays, except for y l-6-beta-D-ribofuranosylimidazo[4,5-d]isothiazole (15a) and oxy-beta-D -ribofuranosyl)imidazo[4,5-d]isothiazole (5e), which showed moderate i nhibition of L1210 cell growth. However, the heterocycles and several of the N-4 glycosylated derivatives were toxic to HFF, KB and L1210 ce lls; compounds with 5-benzylthio substituents were the most cytotoxic agents in this series.