School of Pharmacy, #School of Science and Technology, and ‡School of Biosciences and Biotechnology, University of Camerino , via S. Agostino 1, 62032 Camerino, Italy.
J Med Chem. 2014 Jun 12;57(11):4532-42. doi: 10.1021/jm500458c. Epub 2014 May 20.
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.
已合成了一系列钌（II）芳环配合物，配体为 4-（联苯-4-羰基）-3-甲基-1-苯基-5-吡唑啉酮，以及相关的 1,3,5-三嗪-7-膦杂环戊烷（PTA）衍生物。通过 NMR 和 IR 光谱、ESI 质谱、元素分析和 X 射线晶体学对化合物进行了表征。通过 MTT 测定法测定了四种人癌细胞系中的增殖活性，三种六甲基苯钌配合物的 IC50 值为 9-34 μM，具有剂量和癌细胞系依赖性，而其他金属配合物的活性则低得多。细胞凋亡是这些化合物抗癌活性的机制。事实上，六甲基苯钌配合物激活了半胱天冬酶活性，导致 DNA 片段化、促凋亡蛋白（p27、p53、p89 PARP 片段）的积累，以及抗凋亡蛋白 Bcl-2 的下调。基于生物传感器的结合研究表明，辅助配体对于确定 DNA 结合亲和力至关重要，竞争结合实验进一步表征了相互作用的性质。
