title: Purines. LXX. An extension of the "phenacylamine route" to the syntheses of the 7-N-oxides of 6-mercaptopurine and 6-methylthiopurine, and antileukemic activity of some purine N-oxides.
abstract: A full account is given of the first syntheses of 6-mercaptopurine 7-N-oxide (4) and 6-methylthiopurine 7-N-oxide (5). The synthesis of 4 followed a "phenacylamine route", which started from condensation of 4,6-dichloro-5-nitropyrimidine (15) with N-(4-methoxybenzyl)phenacylamine to form the phenacylaminopyrimidine derivative (11) and proceeded through conversion into the mercapto derivative, intramolecular cyclization between the NO2 nitrogen atom and the phenacyl carbanion to give 6-mercapto-9-(4-methoxybenzyl)purine 7-N-oxide (12), and removal of the 4-methoxybenzyl group. S-Methylation of 12 and removal of the 4-methoxybenzyl group afforded 5. The location of the oxygen function in 4,5, and 12 was confirmed by X-ray crystallographic analysis of 5.H2O, which was shown to exist in the N(7)-OH form (19). A UV spectroscopic approach suggested that the neutral species of 4 exists in H2O as the N(7)-OH tautomer (21), whereas that of 5 exists as an equilibrated mixture of the N(7)-oxide (5) and the N(7)-OH (19) tautomers. In the in vitro bioassay of antileukemic activity against murine L5178Y cells, the N-oxides 4 and 12 were found to be weakly cytotoxic.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: T
authors.initials: T
authors.lastname: Itaya
authors.forename: T
authors.initials: T
authors.lastname: Date
authors.forename: J
authors.initials: J
authors.lastname: Inagaki
authors.forename: F
authors.initials: F
authors.lastname: Nohara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007940:Leukemia L5178 / Q000188:drug therapy; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010087:Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C093739:6-mercaptopurine 7-N-oxide; C093740:6-methylpurine 7-N-oxide; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D010087:Oxides; D011687:Purines; D015122:Mercaptopurine