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

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.

• Authors: Matthias Rothemund, Alexander Bär, Felix Klatt, Sascha Weidler, Leonhard Köhler, Carlo Unverzagt, Claus-D Kuhn, Rainer Schobert
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 97 Pg. 103703 (04 2020) ISSN: 1090-2120 [Electronic] United States
• PMID: 32143017 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Organometallic Compounds
• metallocene
• ASAH1 protein, human
• Acid Ceramidase
• Sphingosine

Topics

• Acid Ceramidase (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line
• Cell Line, Tumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Neoplasms (drug therapy, enzymology, metabolism)
• Organometallic Compounds (chemical synthesis, chemistry, pharmacology)
• Sphingosine (analogs & derivatives, chemical synthesis, pharmacology)