Abstract:
While research in the field of metallo-based chemotherapy drugs is extensive, understanding the effects of pH responsive ligands within these systems is limited. In 2017, the Papish group reported a new class of pH sensitive light-activated metallo drugs that are activated by light-triggered ligand dissociation also known as PACT or photoactivated chemotherapy. Three ruthenium complexes of the type [(N,N’)2Ru(6,6’-dhbp)]Cl2 (the photolabile ligand 6,6’-dhbp = 6,6’-dihydrohybipyridine; 1A: N,N’ = 2,2′-bipyridine (bpy) ; 2A: N,N = 1,10-phenanthroline (phen); 3A: N,N = 2,3-dihydro-[1,4]dioxino[2,3-f ][1,10]phenanthroline (dop)) were synthesized and found to be toxic against various breast cancer cell lines upon irradiation (λ = 450 nm) with compound 3 eliciting EC50 values as low as 4 µM. Phototoxicity indices with 3 were as high as 120, which shows that dark toxicity is limited. The complexes exhibited low overall photodissociation (ΦPD) despite good toxicity suggesting the mode of toxicity is not through a PACT driven pathway. Discussed herin, are the efforts to study the mode of action, physical properties, and which characteristics have the largest impact on light driven toxicity for compounds 1-3 and further investigation into newly developed compounds. The hydrophobicity (Log(Do/w)) and uptake properties of 1-3 are reported. Due to the presence of the protic ligand, 6,6’-dhbp, all of the complexes studied increase in hydrophobicity with pH with 3 being the most hydrophobic (3>2>1). Cellular studies have demonstrated that passive diffusion is the dominant pathway for cellular uptake and compound 3 accumulates in the nuclei of cancer cells (MCF7, MDA-MB-231, and HeLa); however it competes with active transport out of the cell (efflux). Subsequent research has shown that an increase in photodissociation does not result in an increase in toxicity and the primary mode of toxicity is likely via the production of singlet oxygen (1O2); a process known as photodynamic therapy (PDT). Singlet oxygen quantum yields (ΦΔ) were higher for 1-3 upon deprotenation with values as high as 0.87(9) for complex 2. New complexes are also reported which demonstrate improved ΦΔ’s, toxicity, and light selectivity against breast cancer cells demonstrating the importance of studying protic anticancer mettalo drugs.
