The contrasting chemical reactivity of potent isoelectronic iminopyridine and azopyridine osmium(ii) arene anticancer complexes

A wide variety of steric and electronic features can be incorporated into transition metal coordination complexes, offering the prospect of rationally-designed therapeutic agents with novel mechanisms of action. Here we compare the chemical reactivity and anticancer activity of organometallic OsII complexes [Os(η6-arene)(XY)Z]PF6 where arene = p-cymene or biphenyl, XY = N,N′-chelated phenyliminopyridine or phenylazopyridine derivatives, and Z = Cl or I. The X-ray crystal structure of [Os(η6-p-cym)(Impy-OH)I]PF6·0.5CH2Cl2·H2O (Impy-OH = 4-[(2-pyridinylmethylene)amino]-phenol) is reported. Like the azopyridine complexes we reported recently (Dalton Trans., 2011, 40, 10553–10562), some iminopyridine complexes are also potently active towards cancer cells (nanomolar IC50 values). However we show that, unlike the azopyridine complexes, the iminopyridine complexes can undergo aquation, bind to the nucleobase guanine, and oxidize coenzyme nicotine adenine dinucleotide (NADH). We report the first detection of an Os-hydride adduct in aqueous solution by 1H NMR (−4.2 ppm). Active iminopyridine complexes induced a dramatic increase in the levels of reactive oxygen species (ROS) in A549 lung cancer cells. The anticancer activity may therefore involve interference in the redox signalling pathways in cancer cells by a novel mechanism

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os(II) arene complexes [Os(eta(6)-arene)(phenylazopyridine)X](+) in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF(3), OH or NO(2)). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(eta(6)-bip)(2-F-azpy)I]PF(6) (9) and the moderately active complex [Os(eta(6)-bip)(3-Cl-azpy)I]PF(6) (23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs

Heteropentanuclear Oxalato-Bridged n

A series of heteropentanuclear oxalate-bridged Ru(NO)-Ln (4d-4f) metal complexes of the general formula (nBu(4)N)(5)[Ln{RuCl3(-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)[RuCl3(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 (CNMR)-C-13 spectroscopy. X-ray diffraction showed that in 2 and 5 four complex anions [RuCl3(ox)(NO)](2-) are coordinated to Y-III and Dy-III, respectively, with formation of [Ln{RuCl3(-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{OsCl3(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 IC50 values. The highest antiproliferative activity with IC50 values of 20.0 and 22.4M 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