Synthesis, characterization and anti-cancer activity of new ruthenium maltolato and imidazole complexes.

摘要

Several new Ru(III) maltolato (ma) and ethylmaltolato (Ema) complexes have been synthesized, characterized, and tested for biological activity in vitro against MDAMB-435S cells, a human breast cancer cell line. Ru(ma)3 (1) and Ru(Ema)3 (2) were studied in detail using a number of spectroscopic techniques. In particular, the solution 1H NMR spectra of these paramagnetic solids were investigated and, through the use of 2D NMR techniques, structural information about the complexes was determined. These two complexes were then used to synthesize bis-imidazole complexes via removal of one ma or Ema ligand with triflic acid. Trans-[Ru(ma)2(2MeIm)2]CF 3SO3 (10), -[Ru(ma)2(1MeIm) 2]CF3SO3·CH2Cl2 ( 8), and -[Ru(Ema)2(metro)2]CF3SO 3 (11), where 2MeIm = 2-methylimidazole, 1MeIm = 1-methylimidazole, and metro = metronidazole, were synthesized and characterized by X-ray crystallography, while trans-[Ru(ma)2(metro)2]CF 3SO3 (4) was also synthesized and subsequently characterized by X-ray crystallography by another member of our group. Comparison of the 1H NMR data of 8, 10, and 11 with those for the analogous complexes [Ru(ma)2(4MeIm) 2]CF3SO3·CH2Cl2 ( 6), [Ru(Ema)2(4MeIm)2]CF3SO3 (12), and [Ru(Ema)2(2MeIm)2]CF 3SO3 (13), where 4MeIm = 4-methylimidazole, implies that these last three complexes also have trans-configurations. By a similar comparison, [Ru(ma)2(Im)2]CF3SO 3 (7), where Im = imidazole, was found to be a mixture of cis- and trans-isomers that could not be separated.*; The ma and Ema complexes were then tested in vitro using a so-called MTT assay against human breast cancer cells to evaluate their antiproliferatory activity. This assay determines cell viability as a measure of the cell's ability to reduce the yellow MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to the purple formazan in the mitochondria. Complexes containing Ema exhibited lower IC50 values (complex concentration at which cell proliferation has been reduced by 50% after 3 days), than the corresponding ma complexes, and 13 exhibited the lowest value of 500 nM, compared to that for cisplatin (IC50 = 40 muM). Ru-uptake data showed that Ema complexes were taken into Chinese Hamster Ovarian (CHO) cells at levels 4--5 times greater than those for corresponding ma complexes. No significant difference in Ru-uptake was observed between ma complexes with different imidazole ligands when these lacked a nitro group. [Ru(ma) 2(EF5)2]CF3SO3·EtOH ( 14), where EF5 = 2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide, exhibited the highest Ru-uptake of the complexes tested, and was the only complex to exhibit DNA-binding in CHO cells over a 3h incubation period, although it exhibited very low activity in the MTT assay (IC50 value >500 muM).* (Abstract shortened by UMI.); *Please refer to dissertation for diagrams.