Antiviral and Apoptosis Modulating Potential of Fluorinated Derivatives of Uracil

The Epstein-Barr virus (EBV) is the first virus that has been classified as a human oncology virus. The ability of EBV to immortalize the cells of the human body is the highest among all known transforming viruses. Fluorine-containing nucleoside analogs represent a significant class of the chemotherapeutics widely used in the treatment for a lot of diseases. They have been playing a major role in treating tumor and virus either as selective inhibitors of enzymes for cancer or viral replication or as nucleic acid chain terminators which interrupt the replication of cancer cells or a virus.Aim. The purpose of this study was to analyze the potential antiviral and apoptosis modulating activity of fluorinated derivatives of uracil by using in silico and in vitro methods.Materials and methods. Two analogs (compound G26 and G27) on the base of 5-(p-tolilsulfonil)-6(polyfluoroalkyl)uracil were used in the study. The studies were conducted on cultures of Raji (latent infected EBV) and B95-8 (chronically producing virus) B-lymphoma cells. Trypan blue assay, MTT-method, neutral red uptake assay, PCR, flow cytometry, and web-servers PASS, PharmMapper were used.Results. According to PASS prediction, all compounds may possess the antiviral activity and anticancer activity. The in vitro study let to reveal the low level of cytotoxicity of these uracil derivatives. Anti-EBV activity was observed for all compounds and EC50 values were 75 and 65 µg/ml. Using PharmMapper, it has been shown that the targets are enzymes necessary for the replication of viral DNA (protease, kinase) and proteins that provide an apoptotic cascade (MAPK, cytochrome). For compound G27, several peaks on the histogram were observed, which may be evidence of changes in the cell cycle of lymphoblastoid cultures.Conclusions. In this way, the results of the present research shown an antiviral and apoptosis modulating activity of derivatives based on uracil. The data assumed by in silico methods can be used to model the relationship between the structure and activity of substance and predict possible targets of studied chemical compounds. These results can be applied to the further creation of new high-level antiviral agent