Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes

Our work has shown that certain ruthenium(II) arene complexes exhibit promising anticancer activity in vitro and in vivo. The complexes are stable and water-soluble, and their frameworks provide considerable scope for optimising the design, both in terms of their biological activity and for minimising side-effects by variations in the arene and the other coordinated ligands. Initial studies on amino acids and nucleotides suggest that kinetic and thermodynamic control over a wide spectrum of reactions of Ru(II) arene complexes with biomolecules can be achieved. These Ru(II) arene complexes appear to have an altered profile of biological activity in comparison with metal-based anticancer complexes currently in clinical use or on clinical trial.     

Osmium(II) and ruthenium(II) arene maltolato complexes: rapid hydrolysis and nucleobase binding

Density functional calculations show that aquation of [Os(eta6-arene)(XY)Cl]n+ complexes is more facile for complexes in which XY=an anionic O,O-chelated ligand compared to a neutral N,N-chelated ligand, and the mechanism more dissociative in character. The O,O-chelated XY=maltolato (mal) [M(eta6-p-cym)(mal)Cl] complexes, in which p-cym=p-cymene, M=OsII (1) and RuII (2), were synthesised and the X-ray crystal structures of 1 and 22 H2O determined. Their hydrolysis rates were rapid (too fast to follow by NMR spectroscopy). The aqua adduct of the OsII complex 1 was 1.6 pKa units more acidic than that of the RuII complex 2. Dynamic NMR studies suggested that O,O-chelate ring opening occurs on a millisecond timescale in coordinating proton-donor solvents, and loss of chelated mal in aqueous solution led to the formation of the hydroxo-bridged dimers [(eta6-p-cym)M(mu-OH)3M(eta6-p-cym)]+. The proportion of this dimer in solutions of the OsII complex 1 increased with dilution and it predominated at micromolar concentrations, even in the presence of 0.1 M NaCl (conditions close to those used for cytotoxicity testing). Although 9-ethylguanine (9-EtG) binds rapidly to Os(II) in 1 and more strongly (log K=4.4) than to RuII in 2 (log K=3.9), the OsII adduct [Os(eta6-p-cym)(mal)(9EtG)]+ was unstable with respect to formation of the hydroxo-bridged dimer at micromolar concentrations. Such insights into the aqueous solution chemistry of metal-arene complexes under biologically relevant conditions will aid the rational design of organometallic anticancer agents.     

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(η(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(η(6)-bip)(2-F-azpy)I]PF(6) (9) and the moderately active complex [Os(η(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.     

Combination of cysteine- and oligomerization domain-mediated protein immobilization on a surface plasmon resonance (SPR) gold chip surface

Here we report an effective method for protein immobilization on a surface plasmon resonance (SPR) gold chip, describing the combination of cysteine- and oligomerization domain-mediated immobilization of enhanced green fluorescent protein (EGFP) as a model protein for the purpose of orientation-controlled surface density packing. In order to facilitate the oligomerization of EGFP, the dimeric and trimeric constructs derived from GCN4- leucine zipper domain were chosen for multimeric EGFP assembly. For orientation-controlled immobilization of the protein, EGFP modified with cysteine residues showing excellent orientation on a gold chip was used as a starting protein, as previously reported in our earlier study (Anal. Chem., 2007, 79, 2680-2687). Constructs of EGFP with oligomerization domains were genetically engineered, and corresponding fusion proteins were purified, applied to a gold chip, and then analyzed under SPR. The immobilized EGFP density on a gold chip increased according to the states of protein oligomerization, as dimeric and trimeric EGFPs displayed better adsorption capability than monomeric and dimeric forms, respectively. Fluorescence measurement corroborated the SPR results. Taken together, our findings indicated that the combination of cysteine- and oligomerization domain-mediated immobilization of protein could be used in SPR biosensor applications, allowing for an excellent orientation and high surface density simultaneously.     

The Potent Oxidant Anticancer Activity of Organoiridium Catalysts

Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η⁵‐Cp^xbiph)Ir(phpy)(Cl)] ( 1‐Cl ), which contains π‐bonded biphenyltetramethylcyclopentadienyl (Cp^xbiph) and C^N‐chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η⁵‐Cp^xbiph)Ir(phpy)(py)]⁺ ( 1‐py ) aquates slowly, and is more potent (in nanomolar amounts) than both 1‐Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1‐py from rapid reaction with intracellular glutathione. The high potency of 1‐py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H₂O₂ by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.     

Dual triggering of DNA binding and fluorescence via photoactivation of a dinuclear ruthenium(II) arene complex

The dinuclear RuII arene complexes [{(eta6-arene)RuCl}2(mu-2,3-dpp)](PF6)2, arene=indan (1), benzene (2), p-cymene (3), or hexamethylbenzene (4) and 2,3-dpp=2,3-bis(2-pyridyl)pyrazine, have been synthesized and characterized. Upon irradiation with UVA light, complexes 1 and 2 readily underwent arene loss, while complexes 3 and 4 did not. The photochemistry of 1 was studied in detail. In the X-ray structure of [{(eta6-indan)RuCl}2(mu-2,3-dpp)](PF6)2 (1), 2,3-dpp bridges two RuII centers 6.8529(6) A apart. In water, aquation of 1 in the dark occurs with replacement of chloride with biexponential kinetics and decay constants of 100+/-1 min-1 and 580+/-11 min-1. This aquation was suppressed by 0.1 M NaCl. UV or visible irradiation of 1 in aqueous or methanolic solution led to arene loss. The fluorescence of the unbound arene is approximately 40 times greater than when it is complexed. Irradiation of 1 also had a significant effect on its interactions with DNA. The DNA binding of 1 is increased after irradiation. The non-irradiated form of 1 preferentially formed DNA adducts that only weakly blocked RNA polymerase, while irradiation of 1 transformed the adducts into stronger blocks for RNA polymerase. The efficiency of irradiated 1 to form DNA interstrand cross-links was slightly greater than that of cisplatin in both 10 mM NaClO4 and 0.1 M NaCl. In contrast, the interstrand cross-linking efficiency of non-irradiated 1 in 10 mM NaClO4 was relatively low. An intermediate amount of cross-linking was observed when the sample of DNA already modified by non-irradiated 1 was irradiated. DNA unwinding measurements supported the conclusion that both mono- and bifunctional adducts with DNA can form. These results show that photoactivation of dinuclear RuII arene complexes can simultaneously produce a highly reactive ruthenium species that can bind to DNA and a fluorescent marker (the free arene). Importantly, the mechanism of photoreactivity is also independent of oxygen. These complexes, therefore, have the potential to combine both photoinduced cell death and fluorescence imaging of the location and efficiency of the photoactivation process.     

Designing organometallic compounds for catalysis and therapy

Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru(II). Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on η(6)-arene, η(5)-cyclopentadienyl sandwich and half-sandwich complexes of Fe(II), Ru(II), Os(II) and Ir(III) with promising activity towards cancer, malaria, and other conditions.     

Power-efficient impulse radio ultrawideband pulse generator based on the linear sum of modified doublet pulses

We propose a new and power-efficient impulse radio ultawideband (IR-UWB) pulse design concept. The proposed concept is based on a linear sum of modified doublet pulses. The proposed concept is both simulated and experimentally demonstrated. The experimental demonstration employs a photonic scheme that generates the designed pulse using two main steps, mainly optical shaping and differential detection. The optical shaping is performed using a single electro-optic modulator biased in the nonlinear portion of its transfer function, and the differential detection is performed using a balanced photodetector. The generated IR-UWB pulse is fully Federal Communications Commission compliant, even in the highly power-restricted global positioning system band. The proposed optical scheme has potential to be integrated on a compact optical chip and thus suitable for reliable, low-cost, high-speed, short-range UWB wireless access, such as in-building networks.