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Arene-ruthenium(II) acylpyrazolonato complexes: apoptosis-promoting effects on human cancer cells.

Abstract
A series of ruthenium(II) arene complexes with the 4-(biphenyl-4-carbonyl)-3-methyl-1-phenyl-5-pyrazolonate ligand, and related 1,3,5-triaza-7-phosphaadamantane (PTA) derivatives, has been synthesized. The compounds have been characterized by NMR and IR spectroscopy, ESI mass spectrometry, elemental analysis, and X-ray crystallography. Antiproliferative activity in four human cancer cell lines was determined by MTT assay, yielding dose- and cancer cell line-dependent IC50 values of 9-34 μM for three hexamethylbenzene-ruthenium complexes, whereas the other metal complexes were much less active. Apoptosis was the mechanism involved in the anticancer activity of such compounds. In fact, the hexamethylbenzene-ruthenium complexes activated caspase activity, with consequent DNA fragmentation, accumulation of pro-apoptotic proteins (p27, p53, p89 PARP fragments), and the concomitant down-regulation of antiapoptotic protein Bcl-2. Biosensor-based binding studies indicated that the ancillary ligands were critical in determining the DNA binding affinities, and competition binding experiments further characterized the nature of the interaction.
AuthorsRiccardo Pettinari, Claudio Pettinari, Fabio Marchetti, Brian W Skelton, Allan H White, Laura Bonfili, Massimiliano Cuccioloni, Matteo Mozzicafreddo, Valentina Cecarini, Mauro Angeletti, Massimo Nabissi, Anna Maria Eleuteri
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 11 Pg. 4532-42 (Jun 12 2014) ISSN: 1520-4804 [Electronic] United States
PMID24793593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Biphenyl Compounds
  • Coordination Complexes
  • Pyrazolones
  • Ruthenium
  • DNA
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Biphenyl Compounds (chemical synthesis, chemistry, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Coordination Complexes (chemical synthesis, chemistry, pharmacology)
  • DNA (chemistry)
  • Drug Screening Assays, Antitumor
  • Humans
  • Pyrazolones (chemical synthesis, chemistry, pharmacology)
  • Ruthenium
  • Structure-Activity Relationship

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