In the absence of O 2 , the cationic complex, [(phen) 2 Ru(tatpp)Ru(phen) 2 ] 4+ (P 4+ ), undergoes in situ reduction by glutathione (GSH) to form a species that induces DNA cleavage. Exposure to air strongly attenuates the cleavage activity, even in the presence of a large excess of reducing agent (e.g., 40 equiv GSH per P 4+ ) suggesting the complex may be useful in targeting cells with a low oxygen microenvironment (hypoxia) for destruction via DNA cleavage. The active species is identified as the doubly reduced, doubly protonated complex H 2 P 4+ and a carbon-based radical species is implicated in the cleavage action.. We postulate that the pO 2 regulates the degree to which carbon radical forms and thus regulates the DNA cleavage activity.The use of transitions metal complexes in medicine has enjoyed extensive attention given the tremendous success of cisplatin as a chemotherapeutic agent 1 and the ability of many metal complexes to interact with and damage cellular structures, particularly DNA. 2-7 A large number of DNA cleaving metal complexes function via the activation of dioxygen to generate reactive oxygen species (ROS), such as hydroxyl radical and superoxide radical. 8,9 These ROS are ultimately responsible for the DNA cleavage. Others, including cisplatin and certain photoactivated, 10-14 oxidizing 15,16 or hydrolyzing complexes, 8 do not require O 2 to function, but they are also insensitive to the cellular [O 2 ]. Compounds that show enhanced cleavage activity under a low oxygen microenvironment (hypoxia) are rare 17-21 but offer a unique mechanism to target tumor cells under such conditions. These hypoxic tumor cells are often the most resistant to radiotherapy 22,23 and chemotherapy 24,25 (tatpp = 9,11,20,22 -tetraazatetrapyrido[3,2-a: 2′,3′-c: 3″,2″-1: 2‴,3‴-n]-pentacene and phen = 1,10-phenanthroline) shown above (water soluble as the chloride salt) not only induces DNA cleavage in the presence of mild reducing agents but shows enhanced activity under anaerobic conditions. The fact that exposure to air attenuates the cleavage activity suggests that ROS are not responsible for the observed cleavage and that such a complex might be useful in targeting cells under hypoxic conditions. Complex P 4+ is known to intercalate and bind DNA tightly (K b 1.1×10 7 M −1 at 25 mM NaCl). 28,29 The strong interaction with DNA is not unusual for this class of cationic complexes and it has a number of structural similarities to many known metallointercalators 13,14,30-33 including those that are know to thread their way through the DNA double-helix. 34The ability of P 4+ to cut DNA was examined by following the conversion of supercoiled plasmid DNA (form I) to the circular form (form II) or linear form (form III) using agarose gel electrophoresis to separate the products (experimental details given in ESI). As shown in Figure 1, P 4+ alone does not cause appreciable DNA cleavage (lane 2), however, addition of a mild reducing agent such as glutathione (GSH) leads to cleavage activity (lanes 4 &5). ...

The dinuclear ruthenium complex [(phen)2Ru(tatpp)Ru(phen)2]4+ (P; in which phen is 1,10-phenanthroline and tatpp is 9,11,20,22-tetraaza tetrapyrido[3,2-a:2'3'-c:3'',2''-l:2''',3''']-pentacene) undergoes a photodriven two-electron reduction in aqueous solution, thus storing light energy as chemical potential within its structure. The mechanism of this reduction is strongly influenced by the pH, in that basic conditions favor a sequential process involving two one-electron reductions and neutral or slightly acidic conditions favor a proton-coupled, bielectronic process. In this complex, the central tatpp ligand is the site of electron storage and protonation of the central aza nitrogen atoms in the reduced products is observed as a function of the solution pH. The reduction mechanism and characterization of the rich array of products were determined by using a combination of cyclic and AC voltammetry along with UV-visible reflectance spectroelectrochemistry experiments. Both the reduction and protonation state of P could be followed as a function of pH and potential. From these data, estimates of the various reduced species' pKa values were obtained and the mechanism to form the doubly reduced, doubly protonated complex, [(phen)2Ru(H2tatpp)Ru(phen)2]4+ (H2P) at low pH (< or =7) could be shown to be a two-proton, two-electron process. Importantly, H2P is also formed in the photochemical reaction with sacrificial reducing agents, albeit at reduced yields relative to those at higher pH.