Synthesis, Antiproliferative and Antiviral Activity of Imidazo[4,5-d]isothiazole Nucleosides as 5:5 Fused Analogs of Nebularine and 6-Methylpurine Ribonucleoside

• Published in: Journal of medicinal chemistry 1997-02, Vol.40 (5), p.771-784
• Main Authors: Swayze, Eric E, Drach, John C, Wotring, Linda L, Townsend, Leroy B
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Cytomegalovirus - drug effects; General aspects; herpes simplex virus 1; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Molecular Structure; Pharmacology. Drug treatments; Purine Nucleosides - pharmacology; Purines - pharmacology; Ribonucleosides - chemical synthesis; Ribonucleosides - pharmacology; Simplexvirus - drug effects; Thiazoles - chemical synthesis; Thiazoles - pharmacology; Thionucleosides - chemical synthesis; Thionucleosides - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960605z

A series of imidazo[4,5-d]isothiazole nucleosides related to the antibiotic nebularine and the highly cytotoxic 6-methyl-9-β-d-ribofuranosylpurine have been synthesized from the corresponding heterocycles. The sodium salt glycosylation of the imidazo[4,5-d]isothiazoles proceeded smoothly, giving mixtures of N-4 and N-6 regioisomers in generally good yields. The protected derivatives were deblocked using standard conditions to afford the desired imidazo[4,5-d]isothiazole nucleosides, usually as crystalline solids. None of the new nucleosides or heterocycles 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 concentration tested. The N-6 glycosylated imidazo[4,5-d]isothiazoles also were inactive in antiproliferative and cytotoxicity assays, except for 3-methyl-6-β-d-ribofuranosylimidazo[4,5-d]isothiazole (15a) and 5-(benzylthio)-6-(2-deoxy-β-d-ribofuranosyl)imidazo[4,5-d]isothiazole (5e), which showed moderate inhibition of L1210 cell growth. However, the heterocycles and several of the N-4 glycosylated derivatives were toxic to HFF, KB and L1210 cells; compounds with 5-benzylthio substituents were the most cytotoxic agents in this series.