| Autor: |
Walther W; Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin.; Max Delbrück Center for Molecular Medicine, Berlin, Germany., Althagafi D; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland., Curran D; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland., O'Beirne C; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland., Mc Carthy C; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland., Ott I; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Braunschweig., Basu U; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Braunschweig., Büttner B; EPO GmbH Berlin-Buch, Berlin, Germany., Sterner-Kock A; EPO GmbH Berlin-Buch, Berlin, Germany., Müller-Bunz H; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland., Sánchez-Sanz G; Irish Centre of High-End Computing, Grand Canal Quay, Dublin 2, Ireland., Zhu X; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland., Tacke M; School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland. |
| Abstrakt: |
The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3. |
