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)₂Ru(PL)]²⁺ were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1_A: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2_A: N,N = 1,10-phenanthroline (phen) and PL = 6,6'-dhbp; 3_A: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4_A: N,N = bipy and PL = 4,4'-dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5_A: 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_a values for conversion from the acidic form (X_A) to the basic form (X_B) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2_A, 2_B, 3_A, 4_B, and 5_A. All complexes except 5_A showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1_A-4_A and their deprotonated analogues (1_B-4_B), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)₂Ru(H₂O)₂]²⁺. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1_A-5_A showed that complex 3_A is the most cytotoxic complex of this series with IC₅₀ values as low as 4 μM (with blue light) versus two breast cancer cell lines. Complex 3_A is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3_A were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3_A 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_A, 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.

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