Investigation Of Ruthenium (II) Polypyridyl Dimers As Potential Chemotherapeutic Agents
Janaratne, Thamara K
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The exploration of transition metal complexes as chemotherapeutic agents is still a relatively unexplored but promising area of research. Chapter 1 highlights the most successful anticancer drugs and potential drugs based on metal complexes, with an emphasis of platinum and ruthenium complexes. In Chapter 2, the biological activity of a series of novel ruthenium dimers is investigated with special attention given to evaluating their potential as anticancer chemotherapeutic agents. A partial list of the compound prepared includes: [Ru(bpy)(CO)2}2tpphz]4+ (74+), [Ru(bpy)(CH3CN)2}2tpphz]4+ (84+),[Ru(bpy)(C2O4)}2tpphz] (9), [Ru(bpy)(CO)(Cl)}2tpphz]2+ (102+), [(bpy)2Ru(tpphz)Ru(bpy)2]4+ (114+), [(phen)2Ru(tpphz)Ru(phen)2]4+ (124+), [(phen)2Ru(tatpp)Ru(phen)2]4+ (Pp4+), [(phen)2Ru(tatpq)Ru(phen)2]4+ (Qp4+), [(bpy)2Ru(tatpp)Ru(bpy)2]4+ (Pb4+) and [(bpy)2Ru(tatpq)Ru(bpy)2]4+ (Qb4+). Systematic changes in functions, such as overall charge (+4, +2, 0), the presence or absence of labile ligands, long and short bridging ligands between metal centers, and redox inactive (tpphz) and active (tatpp and tatpq) ligands allowed us to complete a structure-activity evaluation of this class of potential anticancer drugs. Most promising were the cationic dimers containing long, redox active bridging ligands, Pp4, Pb4+, Qp4+ and Qb4+, which showed very high DNA binding constants (Kb=107 to 109 M-1) and good cytotoxicity against cancer cell lines (NSCLC). Animal toxicity studies (mice) showed most cationic complexes to be acutely toxic at relatively lower doses. However, the cationic dimers containing the long tatpp or tatpq bridging ligands were well tolerated in mice with maximum tolerable doses in the range of 67-167 mg/kg for Pp4+ and 6.7-17 mg/kg for Qp4+ as the chloride salts. These promising results led to a study of the antitumor activity of Pp4+ and Qp4+ in vivo using a mouse melanoma model. Excitingly, complex Pp4+ seems to inhibit tumor growth in vivo although a little difference in survival times was observed. Nonetheless, the results are promising in that this was an initial screen in which numerous parameters including dosage, frequency of treatment, tumor type, etc., remains unoptimized. The ability of these complexes to damage DNA was evaluated in Chapter 3 by using a plasmid DNA assay that shows if a complex can induce single or double-strand cuts in the DNA molecule. None of the complexes causes any cleavage reactions unless an external reductant is added. However, upon addition of a common biological reductant (glutathione, dithiothritol or ascorbic acid), complex Pp4+ and Qp4+ could be shown to induce single-strand cuts. Importantly, the DNA cleaving ability of Pp4+ is potentiated under anaerobic conditions, showing that the cleavage is not via O2 activation processes. Further studies established that complex Pp4+ is doubly reduced under the assay conditions and the doubly reduced product, denoted H2Pp4+, is the cleavage agent. As this species is oxygen sensitive and readily reoxidized to Pp4+ upon exposure to air, the [O2] 'regulates' the nuclease activity by controlling [H2Pp4+]. The ability of the ruthenium complexes to inhibit or poison topoisomerase I and II was evaluated and is reported in Chapter 4. The intercalating complexes showed the most significant topoisomerase I and II inhibition with complex Pp4+ standing out again for its potent biological activity.