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 η⁶-arene, η⁵-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.

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 both1‐Cland cisplatin towards a wide range of cancer cells. The pyridine ligand protects1‐pyfrom rapid reaction with intracellular glutathione. The high potency of1‐pycorrelates 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 H₂O₂by 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.

We show by x-ray crystallography that the complex trans , trans , trans -[Pt(N ₃ ) ₂ (OH) ₂ (NH ₃ )(py)] ( 1 ) contains an octahedral Pt ^IV center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13–80 x more cytotoxic than the Pt ^II anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine Pt ^II adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA–protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido Pt ^IV complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.