Chemical and Pharmaceutical Bulletin p. 343 - 350 (1992)
Update date:2022-08-05
Topics:
Ogawa
Nishii
Inagaki
Nohara
Saito
Itaya
Fujii
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-1-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°C for 3 h 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 1 N aqueous NaOH, with the chloropyrimidinone 6 were effected in aqueous EtOH at the boiling point for 20 minor at 25-30°C for 3-24 h, giving the 6-phenacylamino-4-pyrimidinones 19a-l in 54-90% yields. On treatment with 2 N 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 19 l 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 1-3 h in the presence of toluene, producing the target N-oxide 5 in 56-89% yields. In the in vitro bioassay of antileukemic activity against murine L5178Y cells, none of the 9-substituted guanine 7-oxides (24a-k and 26) was more effective than the parent, natural N-oxide 5. Within this series, however, the benzyl analogues 24g-k withor without alkoxy functions were more cytotoxic, with IC50's of 13.0-48.0 μg/ml, than the alkyl analogues 24a-f.
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