Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)Ru(PL)] were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp). The thermodynamic acidity of these complexes was measured in terms of two pK values for conversion from the acidic form (X) to the basic form (X) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2, 2, 3, 4, and 5. All complexes except 5 showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1-4 and their deprotonated analogues (1-4), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)Ru(HO)]. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1-5 showed that complex 3 is the most cytotoxic complex of this series with IC values as low as 4 μM (with blue light) versus two breast cancer cell lines. Complex 3 is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3 were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3 and the other complexes tested appears to be higher uptake of the complex as measured by inductively coupled plasma mass spectrometry, and a more hydrophobic complex as compared to 1, which may enhance uptake. These complexes demonstrate proof of concept for dual activation by both low pH and blue light, thus establishing that a pHAMP approach can be used for selective targeting of cancer cells.

The scope of direct substitution of the dithiolene ligand from [M(SCPh)] [M = Ni (1), Pd (2), Pt (3)] to produce heteroleptic species [M(SCPh)L] (n = 1, 2) has been broadened to include isonitriles and dithiooxamides in addition to phosphines and diimines. Collective observations regarding ligands that cleanly produce [M(SCPh)L], do not react at all, or lead to ill-defined decomposition identify soft σ donors as the ligand type capable of dithiolene substitution. Substitution of MeNC from [Ni(SCPh)(CNMe)] by L provides access to a variety of heteroleptic dithiolene complexes not accessible from 1. Substitution of a dithiolene ligand from 1 involves net redox disproportionation of the ligands from radical monoanions, SSCPh, to enedithiolate and dithione, the latter of which is an enhanced leaving group that is subject to further irreversible reactions.

The prospect of a photoexcited chromophore undergoing a reaction that involves transfer of an electron and a proton within an encounter complex with an appropriate acceptor is examined in this work, employing [(bpy)2Ru­(4,4′-dhbpy)]2+ (4,4′-dhbpy = 4,4′-dihydroxy-2,2′-bipyridine, [Ru­(II)­OH]2+) as a chromophore and MQ+ (N-methyl-4,4′-bipyridinium) as an acceptor. The use of an aprotic solvent (CH3CN) allowed unambiguous evaluation of the photoproducts emerging from the encounter complex by using transient absorption spectroscopy in the visible region. While the overall photoproducts reflect transfer of an electron and a proton from [Ru­(II)­OH]2+ to MQ+, detailed analysis suggests that the process occurs via excited-state electron transfer (k q = 7 × 107 M–1 s–1), followed by proton transfer to MQ0 from [Ru­(II)­OH]2+ in solution. The proton transfer process follows pseudo-first order kinetics in the Ru complex and has overall second-order rate constants that are near the diffusion limit. The results are discussed in terms of the free energies for the reactions involved.

Ruthenium complexes exhibit enhanced photodissociation quantum yields due to bulky, weak donor ligands, illustrating the impact of electronics and sterics.

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