Synthesis and biological evaluation of biotin-conjugated anticancer thiosemicarbazones and their iron(III) and copper(II) complexes.

Autor: Kallus S; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria., Uhlik L; Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkeg. 8a, A-1090 Vienna, Austria., van Schoonhoven S; Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkeg. 8a, A-1090 Vienna, Austria., Pelivan K; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria., Berger W; Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkeg. 8a, A-1090 Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', Vienna, Austria., Enyedy ÉA; Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720, Szeged, Hungary., Hofmann T; Department of Environmental Geosciences, University of Vienna, Althanstraße 14, A-1090, Vienna, Austria., Heffeter P; Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkeg. 8a, A-1090 Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', Vienna, Austria. Electronic address: petra.heffeter@meduniwien.ac.at., Kowol CR; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', Vienna, Austria. Electronic address: christian.kowol@univie.ac.at., Keppler BK; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; Research Cluster 'Translational Cancer Therapy Research', Vienna, Austria.
Jazyk: angličtina
Zdroj: Journal of inorganic biochemistry [J Inorg Biochem] 2019 Jan; Vol. 190, pp. 85-97. Date of Electronic Publication: 2018 Oct 19.
DOI: 10.1016/j.jinorgbio.2018.10.006
Abstrakt: Triapine, the most prominent anticancer drug candidate from the substance class of thiosemicarbazones, was investigated in >30 clinical phase I and II studies. However, the results were rather disappointing against solid tumors, which can be explained (at least partially) due to inefficient delivery to the tumor site. Hence, we synthesized the first biotin-functionalized thiosemicarbazone derivatives in order to increase tumor specificity and accumulation. Additionally, for Triapine and one biotin conjugate the iron(III) and copper(II) complexes were prepared. Subsequently, the novel compounds were biologically evaluated on a cell line panel with different biotin uptake. The metal-free biotin-conjugated ligands showed comparable activity to the reference compound Triapine. However, astonishingly, the metal complexes of the biotinylated derivative showed strikingly decreased anticancer activity. To further analyze possible differences between the metal complexes, detailed physico- and electrochemical experiments were performed. However, neither lipophilicity or complex solution stability, nor the reduction potential or behavior in the presence of biologically relevant reducing agents showed strong variations between the biotinylated and non-biotinylated derivatives (only some differences in the reduction kinetics were observed). Nonetheless, the metal-free biotin-conjugate of Triapine revealed distinct activity in a colon cancer mouse model upon oral application comparable to Triapine. Therefore, this type of biotin-conjugated thiosemicarbazone is of interest for further synthetic strategies and biological studies.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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