Heteropentanuclear Oxalato-Bridged nd-4f (n=4, 5) Metal Complexes with NO Ligand: Synthesis, Crystal Structures, Aqueous Stability and Antiproliferative Activity

Abstract

A series of heteropentanuclear oxalate-bridged Ru(NO)-Ln (4d-4f) metal complexes of the general formula (nBu 4 N) 5 [Ln{RuCl 3 (μ-ox)(NO)} 4 ], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were obtained by treatment of (nBu 4 N) 2 [RuCl 3 (ox)(NO)] (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1, 2, and 5 were in addition analyzed by X-ray crystallography, 1 by Ru K-edge XAS and 1 and 2 by 13 CNMR spectroscopy. X-ray diffraction showed that in 2 and 5 four complex anions [RuCl 3 (ox)(NO)] 2- are coordinated to Y III and Dy III, respectively, with formation of [Ln{RuCl 3 (μ-ox)(NO)} 4 ] 5- (Ln=Y, Dy). While Y III is eight-coordinate in 2, Dy III is nine-coordinate in 5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu 4 N + ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium-lanthanide complexes 2-5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC-5) and compared with those obtained for the previously reported Os(NO)-Ln (5d-4f) analogues (nBu 4 N) 5 [Ln{OsCl 3 (ox)(NO)} 4 ] (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes 2-5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d-4f metal complexes 6-9 in terms of IC 50 values. The highest antiproliferative activity with IC 50 values of 20.0 and 22.4μM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP-MS data, indicating five- to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells. The metal makes the difference: A series of heteropentanuclear metal complexes of the general formula (nBu 4 N) 5 [Ln{RuCl 3 (μ-ox)(NO)} 4 ], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were synthesized from (nBu 4 N)[RuCl 3 (ox)(NO)] (1) (see figure). The antiproliferative activity of ruthenium-lanthanide complexes 2-5 in two human cancer cell lines (HeLa and A549) was found to be significantly higher than that for the previously reported Os(NO)-Ln (5d-4f) analogues (nBu 4 N) 5 [Ln{OsCl 3 (μ-ox)(NO)} 4 ] (Ln=Y (6), Gd (7), Tb (8), Dy (9)).