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

Sebastian Kallus, Lukas Uhlik, Sushilla van Schoonhoven, Karla Pelivan, Walter Berger, E. Enyedy, Thilo Hofmann, Petra Heffeter, Christian R. Kowol, Bernhard K. Keppler

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2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)85-97
Number of pages13
JournalJournal of Inorganic Biochemistry
Volume190
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Biotin targeting
  • Metal complexes
  • Thiosemicarbazones
  • Triapine

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

Kallus, S., Uhlik, L., van Schoonhoven, S., Pelivan, K., Berger, W., Enyedy, E., Hofmann, T., Heffeter, P., Kowol, C. R., & Keppler, B. K. (2019). Synthesis and biological evaluation of biotin-conjugated anticancer thiosemicarbazones and their iron(III) and copper(II) complexes. Journal of Inorganic Biochemistry, 190, 85-97. https://doi.org/10.1016/j.jinorgbio.2018.10.006