title: Oxidation of 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide to the corresponding 6-sulfonamide facilitates changes in biologic characterization that include activity against thiopurine-refractory experimental leukemia.
abstract: Preclinical investigations in vivo revealed unexpected differences in the biological characteristics of 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide (sulfenosine, 1) and 2-amino-9-beta-D-ribofuranosylpurine-6-sulfonamide (sulfonosine, 2), two novel but structurally related derivatives of 6-thioguanosine (6TGR). Strikingly, the addition of a fully oxidized sulfur atom at the 6 position of sulfenosine produced a purine derivative (sulfonosine) that was remarkably active against experimental leukemia resistant to treatment with either sulfenosine or 6TGR. This slight structural modification also appeared to influence solubility, scheduling capability, and oral activity as well as penetration of the central nervous system (CNS) and the onset of cellular resistance. These findings underscore the dramatic changes in biologic activity that can be produced by subtle modifications in molecular structure. We trust they may also contribute to the development of improved clinical therapy.
authors.affiliation: ICN Nucleic Acid Research Institute, Costa Mesa, CA 92626.
authors.forename: R A
authors.initials: RA
authors.lastname: Finch
authors.forename: K M
authors.initials: KM
authors.lastname: Vasquez
authors.forename: N B
authors.initials: NB
authors.lastname: Hanna
authors.forename: G R
authors.initials: GR
authors.lastname: Revankar
authors.forename: R K
authors.initials: RK
authors.lastname: Robins
authors.forename: T L
authors.initials: TL
authors.lastname: Avery
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D004351:Drug Resistance; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D010084:Oxidation-Reduction; D011684:Purine Nucleosides / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000627:therapeutic use*; D013872:Thionucleosides / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D013449:Sulfonamides; D013872:Thionucleosides; D006151:Guanosine; C063670:sulfenosine; C063671:sulfonosine; C005783:6-thioguanosine