Towards Establishing The Mechanism Of DNA Cleavage By Redox-active Ruthenium(II) Polypyridyl Complexes

Abstract

In earlier reports, it was established that ruthenium (II) polypyridyl complexes RPCs, [Ru(tatpp)]²⁺ (3²⁺) and [Ru(tatpp)Ru]⁴⁺ (4⁴⁺) show potent antitumor properties in vivo in nude mouse lung cancer models.² These RPC's undergo in vitro reduction by glutathione (GSH) to form a species that induces DNA cleavage. It was also demonstrated that the mechanism of DNA cleavage follows an unusual dependence on dioxygen (O₂) concentration: the increase in cleavage activity of these RPC complexes are inversely proportional to O₂ concentration. In fact, cleavage is quenched in the complete absence of O₂. In this work we currently postulate when 3²⁺ and 4⁴⁺ are singly reduced to species 3+ and 4³⁺, which contains a radical anion localized on the tatpp ligand, abstracts a H atom from the deoxyribose moiety in DNA, leading to DNA cleavage. We describe our results from HPLC analysis of the scission products formed by the degradation of ctDNA and pUC 18 DNA, by carbon radical generated in vitro with 3²⁺and 4⁴⁺. We also show preliminary evidence suggesting that hydrolytic cleavage of the DNA backbone does not occur with 4⁴⁺ but does seem to occur with 3²⁺ From this data we postulate the dual mode of action for DNA cleavage by 3²⁺ could possible explain the reason 3²⁺ has shown enhanced cleavage as compared to 4⁴⁺.