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  4. Novel organometallic ruthenium complexes for selective activation in tumour cells
 
doctoral thesis

Novel organometallic ruthenium complexes for selective activation in tumour cells

Renfrew, Anna Katherine  
2010

In recent years, ruthenium-based antitumour drugs have emerged as an attractive alternative to cisplatin, exhibiting both excellent activity in tumours where cisplatin is of limited use and low general toxicity, leading to reduced side effects. Two ruthenium(III) complexes, KP1019, and NAMI-A, have currently completed Phase I clinical trials and are in, or set to enter, Phase II trials. Expanding on the success of ruthenium(III) complexes, organoruthenium(II) compounds are also attracting increasing attention as anticancer drugs. This thesis presents the chemistry and anticancer activity of a series of organometallic ruthenium (RAPTA) compounds with an η6-arene, a monodentate 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) ligand, with particular emphasis on the development of complexes with selective activity in tumour tissue. Two strategies are described for the development of complexes which exploit the inherent features of a tumour cell: firstly the design of pH selective compounds for specific activity in the acidic tumour environment and secondly micellar complexes for selective uptake by tumour cells with a disordered, 'leaky' structure. The second part of the thesis presents the development of prodrugs that can be activated by a localised external stimulus including the use of UV irradiation to activate phototoxic molecules, and thermoresponsive compounds whose toxicity is improved in a heated tumour cell. The antiproliferative activity of the new compounds was established in vitro across a panel of cell lines and rationalised through evaluation of their stability under physiological conditions and affinity for model cellular targets.

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