Wavelength/nm
3.4 Conclusions
Pseudo-octahedral ‘piano-stool’ organometallic osmium arene complexes have the potential for exploration as anticancer complexes. They are attractive since they provide a hydrophobic arene face amenable to a wide variety of substitutions together with three other variable coordination positions. Both the arene and the other ligands can have a major effect on determining the electron distribution within the complex, controlling their rates of ligand substitution and their redox properties (metal- or ligand-centered). In this chapter, the chelated
azopyridine ligand is both a σ-donor and a strong π-acceptor, i.e. there is a strong
back-donation of electrons from OsII onto the azopyridine ligand producing a large effect on overall reactivity. Iodido complexes were more cytotoxic than the analogous chlorido complexes. In addition, iodido complexes containing p- hydroxyl or p-dimethylamino substituents on the azopyridine chelating ligand (e.g. complexes 3 and 6) were cytotoxic at nanomolar concentrations towards ovarian, lung, breast, colon, prostate, and bladder human cancer cells, an order of magnitude more potent than cisplatin, and (unexpectedly) than their RuII analogues. These iodido complexes are also inert towards hydrolysis. Interestingly, their cytotoxicity was inhibited by pre-treatment of the cells wth N- acetyl-L-cysteine suggesting that reactive oxygen species (ROS) are involved in their mechanism of action, although, unlike their RuII arene azopyridine analogues, the OsIIcomplexes investigated here do not oxidize GSH catalytically. More encouragingly, these OsII complexes exhibited low toxicity and negligible deleterious effects in a HCT-116 tumour xenograft model indicating that they may exhibit a broad therapeutic window.
The organometallic osmium arene azopyridine complex 6, which has nanomolar activityin vitro in a panel of human cancer cell lines, exhibits acivity in vivo against HCT116 human colon cancer xenografts in mice, with negligible
Chapter 3: OsIIArene Azopyridine-R Complexes
the plasma, tumour and normal tissue distribution of6suggest that there is scope to optimize the therapeutic activity using multiple-dose schedules without the risk of off-target toxicity.
3.5 Summary
Iodido osmium(II) complexes [Os(η6
-arene)(XY)I]+, XY = p-hydroxy or p- dimethylamino azopyridine, arene =p-cymene or biphenyl, are potently cytotoxic at nanomolar concentrations towards a panel of human cancer cell lines. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert towards aquation. Their cytotoxic activity appears to involve redox mechanisms. The activity of a potent complex6(FY026)
in vivo versus HCT116 human colon cancer xenografts and the distribution of osmium in plasma and tissues were investigated. Further insight into the mechanism of action of 6 (FY026) was obtained from studies of its redox
potential, its ability to generate Reactive Oxygen Species (ROS) in cells, and the
effect of L-buthionine-sulfoximine (L-BSO), a specific inhibitor of γ-glutamyl-
cysteine synthetase known to reduce intracellular thiol levels,29on the cytotoxicity of the complex.
Chapter 3: OsIIArene Azopyridine-R Complexes
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