Synthesis of an N-aminopyrazinonium analogue of cytidine.

An N-aminated pyrazine analogue of cytidine, in which the pyrimidine N(3) ring nitrogen and C(4) amino group were replaced by a C-amino and an N-amino function, respectively, was prepared as a potential deaminase-resistant cytidine antimetabolite. The nucleoside 1,2-diamino-4-beta-D-ribofuranosylpyrazin-2-onium chloride (6) was a mild cytostatic agent but was neither a substrate for nor an inhibitor of mouse kidney cytidine deaminase. It ionized with a lower pKa than expected. The anion did not undergo the dimerization usually observed with N-imino heterocyclic ylides but unerwent hydrolysis of the 2-amino group to yield a 1-aminopyrazine-2,3-dione nucleoside.

The enhanced sensitivity of mammalian cells to killing by X rays after prolonged exposure to several nitroimidazoles.

Electron affinic compounds, such as misonidazole, preferentially sensitize hypoxic cells to killing by X rays, and are also preferentially cytotoxic to cells deficient in oxygen. Prolonged exposure of cells to misonidazole prior to irradiation results in an increased radiosensitization. This is expressed as the Extra Enhancement Ratio (EER), defined as the ratio of the doses delivered immediately after the addition of the sensitizer or after prolonged incubation, that produce a given biological effect. Chinese hamster V79 cells have been used to investigate this prolonged incubation effect for a variety of 2-nitroimidazoles including misonidazole, desmethylmisonidazole and SR-2508 and as well as two ortho-substituted-4-nitroimidazoles with a bromine or sulfonamide group substituted in the 5-position. A considerable variation was observed in the magnitude of the Extra Enhancement Ratio (EER) produced by pre-incubation with different compounds at concentrations that produce the same sensitizing effect. There is a good correlation between the EER and the measured rate at which the various sensitizers deplete cells of non-protein sulfhydryl compounds. There is also a good correlation between the EER and the fraction of cells killed by the pre-incubation period in the drug.

Newly synthesized hypoxia-mediated drugs as radiosensitizers and cytotoxic agents.

Chinese hamster cells in culture were used to compare the radiosensitizing efficiency and cytotoxicity of misonidazole with several 2, 4 and 5 substituted nitroimidazoles. The two substituted compounds (SR 2508 and SR 2555) are similar to misonidazole in radiosensitizing effectiveness, but are significantly less toxic to hypoxic cells. This reduced cytotoxicity may result from either slower drug penetration or slower removal of non-protein sulfhydryl compounds (NPSH). The compound MJL-1-191-VII (a 4-nitroimidazole) is a much more effective radiosensitizer than would be predicted from its electron affinity. It appears to sensitize by two mechanisms, the first resulting from its electron affinity and the second as consequence of its rapid removal of endogeneous cellular NPSH; which are naturally occurring radioprotective substances.

Synthesis and properties of the sulfonyl analogues of 4(5)-aminoimidazole-5(4)-carboxamide, 4(5)-(formylamino)imidazole-5(4)-carboxamide, guanine, and xanthine.

Reduction of 4(5)-nitroimidazole-5(4)-sulfonamide afforded the sulfonamide analogue of 4(5)-aminoimidazole-5(4)-carboxamide (AICA). This was formylated to afford the sulfonamide analogue of formyl-AICA and was ring closed to the unsubstituted 6-sulfonyl analogue of guanine, 3-aminoimidazo[4,5-e]-1,2,4-thiadizine 1,1-dioxide. Diazotiz ation of the latter afforded the corresponding 6-sulfonyl analogue of xanthine. None of the imidazole-sulfonamides or the purine 6-sulfonyl analogues inhibited the growth of L1210 cells in culture nor were they substrates for or significant inhibitors of human hypoxanthine--guanine phosphoribosyltransferase or milk xanthine oxidase.

Comparative reactivities of esters of oncogenic and nononcogenic purine N-oxides and evidence of the oxidation-reduction reactivity of aromatic nitrenium ions.

Studies on the relative reactivities of esters of oncogenic and nononcogenic members of the purine N-oxide series indicate that, despite similarities in rates of reaction with the solvent, electrophilic cations from oncogenic derivatives are 10- to 100-fold more reactive toward added nucleophiles in vitro than are cations from nononcogenic compounds. The studies provide strong confirmation of an earlier proposal that nitrenium ion contributors of delocalized aromatic cations from 3-acyloxypurines, rather than radical intermediates, are the agents responsible for the oxidizing reactivity of these esters. They demonstrate further that delocalized aromatic nitrenium ions are highly susceptible to reduction by common nucleophiles that are not usually associated with oxidation-reduction reactions. Examples of such behavior with "soft" bases and other oncogenic arylamines indicate the generality of this little recognized property of aromatic nitrenium ions.