Indexed on: 21 Jan '09Published on: 21 Jan '09Published in: Chemical Biology & Drug Design
Nuclear uptake of the simian virus (SV) 40 T antigen is triggered by a specific nuclear localization sequence. However, such a nuclear localization sequence is only poorly taken up by the cytoplasm of cells when administered to the culture medium. Our aim was to improve the cytoplasmic uptake of the SV 40 T antigen nuclear localization sequence. Consequently, we synthesized novel fluorescein isothiocyanate-labelled conjugates containing the nuclear localization sequences of the SV 40 T antigen and either trichlorobenzoic or trifluorobenzoic acid. Applied at 260 microM such halogenated NLS conjugates were nuclearly taken up by 75-85% of U373 and LN18 glioma cells and resulted in cell death. Nuclear staining and cell death were also found at lower concentrations (130 and 65 microM) of halogenated nuclear localization sequence conjugates. By contrast only a low cellular staining rate and no cell death could be observed after co-incubation with a trichlorobenzoic acid or trifluorobenzoic acid-lacking nuclear localization sequence conjugate and free, unbound trichlorobenzoic acid or trifluorobenzoic acid at the high concentration (260 microM). Such small non-radioactive fluorinated and chlorinated nuclear localization sequences may be used as important components for future antiglioma drug development.