Inorganic Chemistry p. 7519 - 7532 (2017)
Update date:2022-08-10
Topics:
Qu, Fengrui
Park, Seungjo
Martinez, Kristina
Gray, Jessica L.
Thowfeik, Fathima Shazna
Lundeen, John A.
Kuhn, Ashley E.
Charboneau, David J.
Gerlach, Deidra L.
Lockart, Molly M.
Law, James A.
Jernigan, Katherine L.
Chambers, Nicole
Zeller, Matthias
Piro, Nicholas A.
Kassel, W. Scott
Schmehl, Russell H.
Paul, Jared J.
Merino, Edward J.
Kim, Yonghyun
Papish, Elizabeth T.
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 (1A: N,N = 2,2′-bipyridine (bipy) and PL, the photolabile ligand, = 6,6′-dihydroxybipyridine (6,6′-dhbp); 2A: N,N = 1,10-phenanthroline (phen) and PL = 6,6′-dhbp; 3A: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f][1,10]phenanthroline (dop) and PL = 6,6′-dhbp; 4A: N,N = bipy and PL = 4,4′-dimethyl-6,6′-dihydroxybipyridine (dmdhbp); 5A: 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 pKa values for conversion from the acidic form (XA) to the basic form (XB) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2A, 2B, 3A, 4B, and 5A. All complexes except 5A showed measurable photodissociation with blue light (λ = 450 nm). For complexes 1A-4A and their deprotonated analogues (1B-4B), 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 1A-5A showed that complex 3A 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 3A is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3A were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3A 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 1A, 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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