2'-O-nitro-1-beta-D-arabinofuranosylcytosine. A new derivative of 1-beta-D-arabinofuranosylcytosine that resists enzymatic deamination and has antileukemic activity.

To overcome the susceptibility of the anticancer drug 1-beta-D-arabinofuranosylcytosine (ara-C) to enzymatic deamination, and hence deactivation, we prepared the 2'-O-nitro-1-beta-D-arabinofuranosylcytosine (termed nitrara-C) and evaluated it for biological activity. Nitrara-C was resistant to enzymatic deamination and inhibited the proliferation of several strains of human leukemic T and B lymphoblasts grown in culture. Moreover, it substantially extended the life spans of mice with L1210 leukemia. Studies with ara-C-resistant human leukemic lymphoblasts deficient in deoxycytidine kinase activity disclosed that the inhibitory activity of the new compound depends on its phosphorylation.

Cytotoxicity of 5-fluoro-5'-O-nitro-2'-deoxyuridine, a new fluorinated pyrimidine derivative, in L1210 cultures.

5-Fluoro-5'-O-nitro-2'-deoxyuridine (FdUMN), a neutral isostere of 5-fluoro-2'-deoxyuridine 5'-monophosphate, inhibited the growth of L1210 cultures. The inhibition of L1210 cultures by FdUMN was prevented by thymidine, but not by 2'-deoxyuridine. Like 5-fluoro-2'-deoxyuridine (FdUrd), FdUMN inhibited the incorporation of 2'-deoxyuridine into DNA, but the onset of this inhibition was not immediate, as was seen with FdUrd. FdUMN did not inhibit the activity of purified thymidylate synthetase from Lactobacillus casei and was a poor inhibitor of thymidylate synthetase activity in homogenates of L1210 ascites cells. However, after incubation with homogenates of these cells and subsequent addition of ATP, FdUMN inhibited this enzyme effectively. These results indicate that intracellular activation of FdUMN is required for its inhibition of thymidylate synthetase.

Synthesis and biological studies of 3-(beta-D-ribofuranosyl)-2,3,-dihydro-6H-1,3-oxazine-2,6-dione, a new pyrimidine nucleoside analog related to uridine.

Reaction of the trimethylsilyl derivative of 2,3-dihydro-6H-1,3-oxazine-2,6-dione (2, "uracil anhydride") with protected 1-O-acetylribofuranoses in the presence of stannic chloride gave the corresponding block nucleosides. 3-(2,3-5-Tri-O-2',2',2'-trichloroethoxycarbonyl-beta-d-ribofuranosyl)-2,3-dihydro-6H-1,3-oxazine-2,6-dione (4c) thus prepared from the protected sugar 3c, 1-O-acetyl-2,3,5-tri-O-(2,2,2-trichloroethoxycarbonyl)ribofuranose, gave, on removal of the protecting groups with zinc dust,3-(beta-d-ribofuranosyl)-2,3-dihydro-6H-1,3-oxazine-2,6-dione (1). The structure of 1 was confirmed by uv, ir, NMR, and CD spectral data and was shown to be an N nucleoside. Uracil anhydride, 2, and, to a lesser extent, its ribonucleoside 1 exert a moderate growth inhibition of mouse leukemia L5178Y, HeLa, and Novikoff hepatoma cells i- culture. Both compounds produce weak inhibition of vaccinia viral replication in HeLa cells.