title: Purines. L. Synthesis and antileukemic activity of the antibiotic guanine 7-oxide and its 9-substituted derivatives.
abstract: A full account is given of the first chemical synthesis of the antitumor antibiotic guanine 7-oxide (5) and its 9-substituted derivatives (24a--k and 26). Coupling of appropriate primary amines (17a--e, g--k) with phenacyl bromide (16) produced, after treatment with HCl, the corresponding N-substituted phenacylamine hydrochlorides (18a--e, g--k). A similar phenacylation of 4-amino-l-butanol (21) failed to give the desired compound 18f, so that 21 was heated with 2-bromomethyl-2-phenyl-1,3-dioxolane (20) at 150-155 degrees C for 3h to furnish, after treatment with HCl, the amino ketal hydrochloride 22 in 40% yield. Deketalization of 22 with hot 2 N aqueous HCl afforded 18f in 96% yield. Condensations of the free bases, generated in situ from the hydrochlorides 18a--l and 1N aqueous NaOH, with the chloropyrimidinone 6 were effected in aqueous EtOH at the boiling point for 20 min or at 25-30 degrees C for 3-24h, giving the 6-phenacylamino-4-pyrimidinones 19a-l in 54-90% yields. On treatment with 2N aqueous NaOH at room temperature for 10-60 min, the nitropyrimidinones 19a--k cyclized to provide the 9-substituted guanine 7-oxides 24a--k in 61-98% yields. A similar alkali-treatment of 191 failed to yield guanine 7-oxide (5). However, removal of the 9-(arylmethyl) group from 24i--k was effected with conc. H2SO4 at room temperature for 1-3h in the presence of toluene, producing the target N-oxide 5 in 56-89% yields.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Research Laboratories, Ikeda Mohando Co., Ltd., Toyama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
authors.forename: M
authors.initials: M
authors.lastname: Nishii
authors.forename: J
authors.initials: J
authors.lastname: Inagaki
authors.forename: F
authors.initials: F
authors.lastname: Nohara
authors.forename: T
authors.initials: T
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Itaya
authors.forename: T
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; C046075:guanine 7-oxide; D006147:Guanine