SURUCO · Sugar-linked Ruthenium-anticancer Complexes

Sugar-linked ruthenium-anticancer complexes

Platinum(II) complex-based chemotherapy is one of the leading treatment options of anticancer treatment. Though severe side effects and a limited number of tumours can be cured, platinum compounds are used in majority of chemotherapeutic schemes. Many different drug design strategies have been used in attempts to improve the properties of anticancer drugs, including the development of compounds that undergo activation in the tumour, targeted and targeting approaches, etc. In recent years, ruthenium(II)- and osmium(II)-arene complexes have become the focus of interest and some examples appear to be promising anticancer drug candidates. The metal-arene motif is an excellent scaffold for rational drug design, with the potential to fine-tune the anticancer activity and other drug-relevant properties such as stability and solubility. Targeting drugs to cancer cells via metabolic processes is one of the major approaches to stop malignant progression in a selective fashion. Cancer cells usually display enhanced glucose uptake under hypoxic conditions, due to overexpression of glycolytic enzymes and glucose transporters, as compared to healthy cells. To take advantage of this effect ruthenium(II)- and osmium(II)-arene compounds and trinuclear carbonyl clusters bearing sugar-derived bicyclophosphite ligands were prepared with dichlorido and chelating biscarboxylates co-ligands. The influence of the carbohydrate moiety on the accumulation and uptake of the ruthenium complexes was studied by derivatisation of the arene with an anthracene moiety (a fluorescent group), with the sugar-ligand system compared to a benchmark PTA derivatives. It was found that a significant increase in cellular uptake in case of the carbohydrate containing complex was observed (monitored by fluorescent microscopy), indicating that the new ligand helps to increase the accumulation of the drug in the cancer cells. While the ruthenium(II) and osmium(II)-arene complexes were not strongly cytotoxic the cluster compounds showed exceptionally high cytotoxicity on the human A2780, A2780cisR ovarian carcinoma cell lines. Such high cytotoxicity in the case clusters with one or two sugar ligands may be explained by the presence of an unsubstituted ruthenium centre and the possible interaction of this centre with biological targets and also due to carbon monoxide releasing properties. The CO releasing potential was studied by myoglobin assay and energy-dependent electrospray ionisation mass spectrometry (EDESI) showing stepwise loss of CO. Overall, all research objectives of the project were achieved and training of the new skills described in the personal career development plan were received.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз