Arene–Ruthenium(II)Acylpyrazolonato Complexes:Apoptosis-Promoting Effects on Human Cancer Cells.

A seriesof ruthenium(II) arene complexes with the 4-(biphenyl-4-carbonyl)-3-methyl-1-phenyl-5-pyrazolonateligand, and related 1,3,5-triaza-7-phosphaadamantane (PTA) derivatives,has been synthesized. The compounds have been characterized by NMRand IR spectroscopy, ESI mass spectrometry, elemental analysis, andX-ray crystallography. Antiproliferative activity in four human cancercell lines was determined by MTT assay, yielding dose- and cancercell line-dependent IC50values of 9–34 μMfor three hexamethylbenzene–ruthenium complexes, whereas theother metal complexes were much less active. Apoptosis was the mechanisminvolved in the anticancer activity of such compounds. In fact, thehexamethylbenzene–ruthenium complexes activated caspase activity,with consequent DNA fragmentation, accumulation of pro-apoptotic proteins(p27, p53, p89 PARP fragments), and the concomitant down-regulationof antiapoptotic protein Bcl-2. Biosensor-based binding studies indicatedthat the ancillary ligands were critical in determining the DNA bindingaffinities, and competition binding experiments further characterizedthe nature of the interaction. [ABSTRACT FROM AUTHOR]