2. Academic Validation
  3. N-Metallocenoylsphingosines as targeted ceramidase inhibitors: Syntheses and antitumoral effects

N-Metallocenoylsphingosines as targeted ceramidase inhibitors: Syntheses and antitumoral effects

  • Bioorg Chem. 2020 Apr:97:103703. doi: 10.1016/j.bioorg.2020.103703.
Matthias Rothemund 1,  Alexander Bär 1,  Felix Klatt 2,  Sascha Weidler 3,  Leonhard Köhler 1,  Carlo Unverzagt 3,  Claus-D Kuhn 2,  Rainer Schobert 4
Affiliations

Affiliations

  • 1 Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany.
  • 2 Gene Regulation by Non-Coding RNA, Elite Network of Bavaria and University of Bayreuth, Universitaetsstr. 30, 95447 Bayreuth, Germany.
  • 3 Bioorganic Chemistry, University of Bayreuth, Universitaetsstr. 30, 95447 Bayreuth, Germany.
  • 4 Department of Chemistry, University Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany. Electronic address: [email protected].
PMID: 32143017 DOI: 10.1016/j.bioorg.2020.103703
Abstract

Three N-metallocenoylsphingosines with variance in the central metal (Fe, Co, Ru), the charge (neutral or cationic), and the arene ligands (Cp2, Cp*Ph) were synthesized from serine and metallocene carboxylic acids as substrate-analogous inhibitors of human acid Ceramidase (AC). Their inhibitory potential was examined using the recombinant full length ASAH1 Enzyme, expressed and secreted from High Five insect cells, and the fluorescent substrate Rbm14-12. All complexes inhibited AC, most strongly so ruthenium(II) complex 13a. Some antitumoral effects of the complexes, such as the interference with the microtubular and F-actin Cytoskeleton of Cancer cells, were correlated to their AC-inhibition, whereas Others, e.g. their cytotoxicity and their induction of Caspase-3/-7 activity in Cancer cells, were not. All complexes accumulated preferentially in the lysosomes of Cancer cells like their target AC, arrested the cells in G1 phase of the cell cycle, and displayed cytotoxicity with mostly single-digit micromolar IC50 values while inducing Cancer cell Apoptosis.

Keywords

Anticancer agents; Ceramidase inhibitors; Colocalization; Organometallic drugs; Sphingolipids.

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