Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-β-D-arabinofuranosyladenine

• Published in: Journal of medicinal chemistry 1992-01, Vol.35 (2), p.397-401
• Main Authors: MONTGOMERY, J. A, SHORTNACY-FOWLER, A. T, CLAYTON, S. D, RIORDAN, J. M, SECRIST, J A
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - chemical synthesis; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - pharmacology; Carbohydrates. Nucleosides and nucleotides; Chemistry; Escherichia coli - enzymology; Exact sciences and technology; HIV - drug effects; Humans; Leukemia P388 - drug therapy; Mice; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Purine-Nucleoside Phosphorylase - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects; Vidarabine - analogs & derivatives; Vidarabine - chemical synthesis; Vidarabine - metabolism; Vidarabine - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00080a029

The synthesis of 2-halo-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenines (4b and 4d) by coupling the 2,6-dihalopurine with 3-acetyl-5-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (2) followed by replacement of the 6-halogen with concomitant removal of the acyl blocking groups is described. 2-Fluoroadenine derivative 4g had to be prepared by the diazotization-fluorination of 2-aminoadenine nucleoside 4e. All three nucleosides provided good increases in life span of mice inoculated with P388 leukemia. The best results were obtained when the compounds were administered q3h x 8 on days 1, 5, and 9 after implantation of the leukemia cells. The 2',3'-dideoxynucleoside 5b, prepared by deacetylation of 4f and deoxygenation of the resultant 4h followed by removal of the benzoyl group of 5a, was slightly active against HIV in cell culture.