New precious metal compounds in cancer therapy

Includes abstract.Includes bibliographical references (leaves 139-160).Cisplatin is one of the most effective cancer medications currently available. However, it is seriously limited by patient toxicity and drug resistance. As such, there is a real need for altemative treatments. Some compounds of gold(l) have been found to be biologically active in various contexts, including in killing cancer cells. The metal centres gold(lIl) and rhodium(lI) are isoelectronic to the platinum(ll) centre in cisplatin, and some of their compounds have been shown to have biological activity. The aims of this work were to prepare pyridinecontaining complexes of the three metal centres gold(I), gold(llI) and rhodium(I), and assess these complexes for in vitro anti-cancer activity. Phenyl pyridine and ferrocenylpyridine complexation was achieved with all three metal centres described above. With gold(I), either a chloride or pentafluorophenyl counter-anion was used. The rhodium(l) complexes contained 1,5-cyclooctadiene moieties linked to the metal centre via diene complexation, and a chloride counter-anion. Phenylpyridine complexes of gold(lIl) were achieved via standard reaction with tetrachloroaurate anion. However, the analogous ferrocenylpyridine complexes display unusually low stability and other unexpected physical properties, and are believed to be highly novel chlorobridged gold dimers. The 4-phenylpyridine complex of rhodium(l) was initially found to be active against cancer cells in vitro. It was, however, demonstrated that this activity was actually due to the breakdown product of this compound in DMSO. It was found that this breakdown product interacts with DNA, implying a similar mechanism of action to cisplatin. This is supported by the fact that a cisplatin-resistant cell line displays hjgh cross-resistance against this product. (4-Phenylpyridine)gold(l) (pentafluorophenyl) was also found to be extremely active against cell lines in vitr