title: 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.
authors.affiliation: School of Pharmacy, #School of Science and Technology, and ‡School of Biosciences and Biotechnology, University of Camerino , via S. Agostino 1, 62032 Camerino, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pettinari
authors.forename: Claudio
authors.initials: C
authors.lastname: Pettinari
authors.forename: Fabio
authors.initials: F
authors.lastname: Marchetti
authors.forename: Brian W
authors.initials: BW
authors.lastname: Skelton
authors.forename: Allan H
authors.initials: AH
authors.lastname: White
authors.forename: Laura
authors.initials: L
authors.lastname: Bonfili
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cuccioloni
authors.forename: Matteo
authors.initials: M
authors.lastname: Mozzicafreddo
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecarini
authors.forename: Mauro
authors.initials: M
authors.lastname: Angeletti
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Eleuteri
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D056831:Coordination Complexes; D047069:Pyrazolones; D012428:Ruthenium; D004247:DNA