Ruthenium-based PACT compounds based on an N,S non-toxic ligand: a delicate balance between photoactivation and thermal stability

Abstract

In photoactivated chemotherapy, the photocleavable protecting group that prevents the bioactive compound from interacting with biomolecules in the dark is sometimes cytotoxic, which makes interpretation of phototoxicity challenging. For ruthenium polypyridyl complexes new, non-toxic protecting ligands that prevent a toxic metal complex from binding to biomolecules in the dark, but that can be efficiently photosubstituted upon visible light irradiation to recover the high toxicity of the metal complex, are necessary. In this work, we report on the synthesis, stereochemical characterization and cytotoxicity of a series of polypyridyl complexes; [Ru(bpy)2(mtpa)](PF6)2 ([1](PF6)2, bpy = 2,2’-bipyridine), [Ru(bpy)(dmbpy)(mtpa)](PF6)2 ([2](PF6)2, dmbpy = 6,6’-dimethyl-2,2’-bipyridine), and [Ru(dmbpy)2(mtpa)](PF6)2 ([3](PF6)2) based on the non-toxic 3-(methylthio)propylamine protecting ligand (mtpa). The number of methyl groups had a crucial effect on the photochemistry and cytotoxicity of these complexes. The non-strained complex [1]2+ was not capable of fully releasing mtpa and was not phototoxic in lung cancer cells (A549). In the most strained complex [3]2+, thermal stability was lost, leading to poor photoactivation in vitro and a generally high toxicity also without light activation. The heteroleptic complex [2]2+ with intermediate strain showed, upon blue light irradiation, efficient mtpa photosubstitution and increased cytotoxicity in cancer cells, but photosubstitution was not selective. Overall, fine-tuning of the lipophilicity and steric strain of ruthenium complexes appears as an efficient method to obtain phototoxic ruthenium-based photoactivated chemotherapeutic prodrugs, at the cost of synthetic simplicity and photosubstitution selectivity.