Nucleosides of 1,4-thiazin-3-one and derivatives as tetrahedral intermediate analogs of enzymes in pyrimidine nucleoside metabolism

• Published in: Journal of medicinal chemistry 1988-08, Vol.31 (8), p.1575-1579
• Main Authors: Marcus, E. Ted, Gundy, Afaf, Levenson, Corey H, Meyer, Rich B
• Format: Article
• Language: English
• Subjects: Animals; Carbohydrates. Nucleosides and nucleotides; Carbon-Nitrogen Ligases; Chemical Phenomena; Chemistry; Cytidine Deaminase - antagonists & inhibitors; Exact sciences and technology; Humans; Leukemia L1210 - drug therapy; Leukemia, Lymphoid - drug therapy; Ligases - antagonists & inhibitors; Mice; Nucleosides - chemical synthesis; Nucleosides - therapeutic use; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Pyrimidine Nucleosides - metabolism; Structure-Activity Relationship; Thiazines - chemical synthesis; Thiazines - therapeutic use; Tumor Cells, Cultured - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00403a015

Reaction of the trimethylsilylated derivative of 1,4-thiazin-3-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of SnCl4 gave, after deblocking, 4-beta-ribofuranosyl-1,4-thiazin-3-one (8). Treatment of 1,4-thiazin-3-one with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranose in the presence of sodium hydride provided, after deblocking, the corresponding 2-deoxy-beta-D-ribofuranosyl derivatives (19). Oxidation of 4-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,4-thiazin-3-one (7) with 1 equiv of m-chloroperbenzoic acid resulted in 4-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,4-thiazine-2,3-dione (9) and 4-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,4-thiazin-3-one 1-oxide (10). Evidence is presented that indicates that the oxidation of the thiazine at the 2-position is due to a Pummerere rearrangement. The new compounds failed to show significant activity against tumor cell lines in culture, L1210 cells in vivo, virus cytotoxicity in cell culture, or cytidine deaminase.