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It is well-known that the introduction of vinyl and ethynyl moieties into nucleosides is of crucial importance for cytostatic, antiviral, or other biological activities. In this study 6- and 8-vinyl-and -ethynyluridine and -adenosine were prepared by a general procedure involving the palladium-catalyzed cross-coupling of trimethylsilylacetylene or vinyltributyltin. The introduction of a vinyl group at C-6 of uridine or an ethynyl group at C-8 of adenosine resulted in nucleoside derivatives showing cytostatic activity against several murine and/or human tumor cell lines. Interestingly, 8-vinyladenosine had pronounced selective inhibitory effects on human (Molt/4F and MT-4) versus murine (L1210 and FM3A) tumor cell lines.

No abstract is provided for this article.

E-5-(2-Bromovinyl)-2'-deoxyuridine (BrvdUrd) and E-5-(2-iodovinyl)-2'-deoxyuridine (IvdUrd) are among the most potent and selective inhibitors of herpes simplex virus type 1 (HSV-1) replication. To elucidate the site of inhibition, we examined whether the halovinyl analogs are incorporated into DNA using two approaches. (i) In assays with purified DNA polymerases omitting dTTP from the reaction system, addition of either BrvdUTP or IvdUTP increased the polymerization reaction, indicating that these two analog triphosphates can be alternate substrates. (ii) When HSV-1-infected Vero cells were grown in the presence of either BrvdUrd or IvdUrd, there was an increase in the density of both the viral and cellular DNA. The viral DNA had 40% of its thymidine moiety substituted by IvdUrd when the concentration of [125I]IvdUrd was 24 microM (in the absence of added thymidine). At 30 microM BrvdUrd and 1 microM [2-14C]thymidine, the viral DNA had only 11% of its thymidine moiety substituted by BrvdUrd, presumably because of the presence of added thymidine. Following digestion of [125I]IvdUrd-substituted DNA with DNase 1, venom phosphodiesterase, and alkaline phosphatase, the radioactivity co-migrated with nonradioactive IvdUrd in thin layer chromatography. Under similar conditions, no detectable incorporation of either [125I]IvdUrd or BrvdUrd into mock-infected Vero cell DNA was observed. Thus, IvdUrd and BrvdUrd are incorporated into DNA of HSV-1 infected cells but not into DNA of uninfected cells.

The novel pyrimidine derivatives 1-6 of 2,3-dibenzyl-4,5-didehydro-5, 6-dideoxy-L-ascorbic acid were synthesized by the condensation of pyrimidine bases with 5,6-diacetyl-2,3-dibenzyl-L-ascorbic acid (DDA). Both N-9 (7) and N-7 (8) regioisomers were obtained in the reaction of 6-chloropurine with 5-acetyl-6-bromo-2, 3-dibenzyl-L-ascorbic acid (ABDA), while the reaction of 6-(N-pyrrolyl)purine with ABDA afforded exclusively the N-9 isomer 9. Structures of all newly prepared compounds were deduced from the chemical shifts in (1)H and (13)C NMR spectra, as well as connectivities in 2D homo- and heteronuclear correlation spectra. An unambiguous proof of the structure and conformation of 7 was obtained by X-ray crystallographic analysis. Compounds 1-9 were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), murine leukemia (L1210/0), murine mammary carcinoma (FM3A), and human T-lymphocytes (Molt4/C8 and CEM/0), as well as antiviral activities against varicella-zoster virus (TK(+)VZV and TK(-)VZV) and cytomegalovirus (CMV). The compound 6 containing a trifluoromethyl-substituted uracil ring exhibited marked antitumor activity. The N-7-substituted purine regioisomer 8 had greater inhibitory effects on the murine L1210/0 and human CEM/0 cell lines than the N-9 isomer 7. Compound 9 with the 6-purine-substituted pyrrolo moiety had a more pronounced selective cytostatic activity against human (Molt4/C8 and CEM/0) cell lines than murine (L1210/0 and FM3A/0) and human (MiaPaCa2, MCF7, HeLa, and Hep2) tumor cell lines and normal fibroblasts (Hef522). The compound 6 exhibited the most potent antiviral activities against TK(+)VZV, TK(-)VZV, and CMV, albeit at concentrations that were only slightly lower than the cytotoxic concentrations.