Antiproliferační aktivity 6-benzyladenosidů a jejich pro-drugs. (Antiproliferative activity of 6-benzylanosides and their pro-drug forms)

The cytokinins are one of the major groups of phytohormones, which control key processes during plant growth and development. They were first identified as a factor that promotes cell division in the presence of auxin and sustained growth in cultured plant cells. Systematic screening and testing on various cancer cell lines of the in vitro cytotoxicity of 6-benzyladenosine, substituted differently on the benzyl ring have been done. The most promising compound of this study, 6-(2-hydroxy-3-methoxybenzylamino)purine riboside, has been tested for its antitumour activity against cancer cell lines derived from various tumors. The IC50 data obtained from a calcein AM viability/cytotoxicity or MTT assay showed the interesting cytotoxic properties of this substance in contrast to other very similar derivatives which displayed much lower activity in this assay. Therefore, these results support the potential use of this compound in cancer, especially in the treatment of leukaemias. The 6-benzylaminopurine riboside, 6-(2-hydroxy-3-methoxybenzylamino)purine riboside, and both prodrug forms reduced the frequency of S-phase cells of the cancer cell line CEM in antiproliferation assays. Further observed cellular effects included inhibition of DNA and RNA synthesis. The leading compound 6-(2-hydroxy-3-methoxybenzylamino)purine riboside as well as its mono-acetylated PD01 and tetra-acetylated PD02 pro-drug forms, respectively, were tested for its bioavailability after the oral administration to eight week old female Balb/c mice. We have confirmed that -(2-hydroxy-3-methoxybenzylamino)purine riboside is not bioavailable, but a acetylated pro-drugs exhibited high bioavailability, the plasmatic concentrations of free 6-(2-hydroxy-3-methoxybenzylamino)purine reached therapeutic ranges (9.3 ?M/5.7 ?M), 2 or 4 hours following the prodrug administration. Anticancer activity of pro-drugs was also analyzed in vivo using P388D1 and K562 leukemia models.

Supported by grants awarded by the Czech Ministry of Education (MSM 6198959216 and LC07017).