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.

Applications of Purine Ring Opening in the Synthesis of Imidazole, Pyrimidine, and New Purine Derivatives

“…In contrast to this, ammonia in hot ethanolic solution under pressure added to the C ‐8 position, giving 288 (Scheme 49). [219,220] …”

“…In contrast to this, ammonia in hot ethanolic solution under pressure added to the C-8 position, giving 288 (Scheme 49). [219,220] Heteroamines A-H are found in plant Heterostemma browni used in folk medicine for the treatment of tumors. Heteroamines A-C 289 a-c can be readily obtained from guanine [221] or 2-amino-6-chloropurine [222] and, due to the activated imidazolium ring, can be converted to heteroamines F-H 290 a-c via ring opening with dilute aqueous ammonia (Scheme 50).…”

Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents

“…N -oxides 210 and 211 on the other hand have been shown to be weakly cytotoxic and have not be shown to possess any antimicrobial activity. [171] Studies by Parra and coworkers [172] showed that hypoxanthine 3- N -oxide 213 is the main chemical that elicits alarm reactions in zebrafish. These results are based on the observation of an efficaciously induced fear reactions and increase in the number of erratic movement episodes and jumps upon administration of this compound to zebrafish.…”

Oxidation chemistry of adenine N1-oxide, a potent oncogenic agent, at a pyrolytic graphite electrode

“…The oxidative transformation of purines into their N-oxide derivatives which are potent oncogenic agents introduces the possibility that such derivatives play an important role in various biological and clinical processes. [1][2][3] The presence of the N-oxide group in purines has been found to induce antibiotic activity. 4 Several purine N-oxides have been reviewed in relation to their oncogenic 5 and antitumor properties.…”