3-deazauridine and 3-deazacytidine

Novel 3-substituted analogues of 4-amino-1-beta-D-ribofuranosyl-2(1H)-pyridinone (3-deazacytidine, 3) and 4-hydroxy-1-beta-D-ribofuranosyl-2(1H)-pyridinone (3-deazauridine, 4) have been synthesized and tested for antitumor and antiviral activity. Thus the 3-chloro (9a), 3-bromo (9b), and 3-nitro (9c) analogues of 3 and the 3-chloro (9d), 3-bromo (9e), and 3-nitro (9f) analogues of 4 were prepared by standard glycosylating procedures. Novel requisite heterocycles 4-amino-3-chloro-2(1H)-pyridinone (7a) and 4-amino-3-bromo-2(1H)-pyridinone (7b) were prepared by halogenating 4-amino-2(1H)-pyridinone (5). Requisite heterocycles 4-amino-3-nitro-2(1H)-pyridinone (7c), 3-chloro-4-hydroxy-2(1H)-pyridinone (7d), 3-bromo-4-hydroxy-2(1H)-pyridinone (7e), and 4-hydroxy-3-nitro-2(1H)-pyridinone (7f) were synthesized by known procedures from 4-hydroxy-2(1H)-pyridinone (6). Structure proof of target nucleosides was provided by independent synthesis, 1H NMR, and UV. Compounds 9a-f were devoid of activity against intraperitoneally implanted L1210 leukemia in mice. Compound 9f displayed significant activity against rhinovirus type 34 grown in WISH cells. 4-Amino-3-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (1) displayed good activity against intraperitoneally implanted P388 leukemia in mice, but it was devoid of activity against M5076 sarcoma, amelanotic (LOX) melanoma xenograft, and subrenal capsule human mammary carcinoma MX-1 xenograft in mice. Compound 1 also displayed significant activity against rhinovirus type 34.

Topics: 3-Deazauridine; Animals; Antineoplastic Agents; Antiviral Agents; Cell Line; Cell Survival; Cytidine; Female; Humans; Indicators and Reagents; Leukemia L1210; Leukemia P388; Mice; Microbial Sensitivity Tests; Molecular Structure; Neoplasm Transplantation; Rhinovirus; Structure-Activity Relationship; Subrenal Capsule Assay; Transplantation, Heterologous; Tumor Cells, Cultured; Uridine

New method for a synthesis of diazaphenoxathiin skeleton from 3-deazauracil derivatives is reported. It became possible to convert 3-deazauridine to 3-deazacytidine via an excellent intermediate "diazaphenoxathiin sulfoxide derivative".

Topics: 3-Deazauridine; Chemical Phenomena; Chemistry; Cytidine; Fluorescent Dyes; Heterocyclic Compounds; Hydrolysis; Oxathiins; Pyrimidine Nucleosides; Ribonucleosides; Uridine

The circular dichroism and electronic absorption of three simple model systems for cytidine and uridine have been measured to 190 nm. The molecular spectral properties (excitation wavelengths, oscillator strengths, rotational strengths, and polarization directions) and electronic transitional patterns were investigated by using wave functions of the entire nucleoside with the goal of establishing the reliability of the theoretical method. The computed electronic absorption quantities were shown to be in satisfactory agreement with experimental data. It was found that the computed optical rotatory strengths of the B2u and E1u electronic transitions and lowest observed n-pi transition are in good agreement with experimental values. Electronic transitions were characterized by their electronic transitional patterns derived from population analysis of the transition density matrix. The theoretical rotational strengths associated with the B2u and E1u transitions stabilize after the use of just a few singly excited configurations in the configuration interaction basis and, hypothetically, are more reliable as indicators of conformation in pyrimidine nucleosides related to cytidine.

Topics: 3-Deazauridine; Antineoplastic Agents; Circular Dichroism; Cytidine; Deoxyuridine; Nucleic Acid Conformation; Spectrophotometry, Ultraviolet; Spectrum Analysis; Uridine

PCILO computations ahve been carried out on the conformational properties of 3-deazapyrimidine nucleosides namely: 3-deazauridine and 3-deazacytidine. These nucleoside analogs result as a consequence of the replacement of N(3) by a carbon atom and they become nucleoside antibiotics having cytostatic and antiviral properties. Both C(2')-endo and C(3')-endo sugar geometries have been considered and the results indicate that the conformational preferences of these nucleoside antibiotics are very similar to those of their parent nucleosides and more particularly so in the situations that occur in aqueous solutions. The important biological significance of the results has been discussed.

Topics: 3-Deazauridine; Anti-Bacterial Agents; Chemical Phenomena; Chemistry; Cytidine; Hydrogen Bonding; Molecular Conformation; Structure-Activity Relationship; Uridine; X-Ray Diffraction