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)](PF 6 ) 2 ([1](PF 6 ) 2 , bpy = 2,2'-bipyridine), [Ru(bpy)(dmbpy)(mtpa)](PF 6 ) 2 ([2](PF 6 ) 2 , dmbpy = 6,6'-dimethyl-2,2'-bipyridine), and [Ru(dmbpy) 2 (mtpa)](PF 6 ) 2 ([3](PF 6 ) 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.

Cyclometallated ruthenium complexes typically exhibit red‐shifted absorption bands and lower photolability compared to their polypyridyl analogues. They also have lower symmetry, which sometimes makes their synthesis challenging. In this work, the coordination of four N,S bidentate ligands, 3‐(methylthio)propylamine (mtpa), 2‐(methylthio)ethylamine (mtea), 2‐(methylthio)ethyl‐2‐pyridine (mtep), and 2‐(methylthio)methylpyridine (mtmp), to the cyclometallated precursor [Ru(bpy)(phpy)(CH 3 CN) 2 ] + (bpy=2,2′‐bipyridine, Hphpy=2‐phenylpyridine) has been investigated, furnishing the corresponding heteroleptic complexes [Ru(bpy)(phpy)(N,S)]PF 6 ([ 2 ]PF 6 –[ 5 ]PF 6 , respectively). The stereoselectivity of the synthesis strongly depended on the size of the ring formed by the Ru‐coordinated N,S ligand, with [ 2 ]PF 6 and [ 4 ]PF 6 being formed stereoselectively, but [ 3 ]PF 6 and [ 5 ]PF 6 being obtained as mixtures of inseparable isomers. The exact stereochemistry of the air‐stable complex [ 4 ]PF 6 was established by a combination of DFT, 2D NMR, and single‐crystal X‐ray crystallographic studies. Finally, [ 4 ]PF 6 was found to be photosubstitutionally active under irradiation with green light in acetonitrile, which makes it the first cyclometallated ruthenium complex capable of undergoing selective photosubstitution of a bidentate ligand.

The importance of transition metal catalysis is exemplified by its wide range of applications, for example in the synthesis of chemicals, natural products, and pharmaceuticals. However, one relatively new application is for carrying out new‐to‐nature reactions inside living cells. The complex environment of a living cell is not welcoming to transition metal catalysts, as a diverse range of biological components have the potential to inhibit or deactivate the catalyst. Here we review the current progress in the field of transition metal catalysis, and evaluation of catalysis efficiency in living cells and under biological (relevant) conditions. Catalyst poisoning is a ubiquitous problem in this field, and we propose that future research into the development of physical and kinetic protection strategies may provide a route to improve the reactivity of catalysts in cells.

Gold catalysts exhibit poor compatibility with cellular components. We show that encapsulation of a gold catalyst within the cavity of a supramolecular cage improves the reactivity of the gold complex under biological conditions. The gold complex catalyzes an intramolecular hydroarylation to produce a fluorescent dye. The encapsulated gold is able to produce this dye in higher yields compared to the free gold under aqueous aerobic conditions and in the presence of biological additives.The substrate was found to be highly cytotoxic, meaning that a very low substrate concentration of 1 μM is required to carry its transformation inside living cells; however, catalysis in cell culture media carried out at micromolar range is found to be inhibited. Although this specific reaction cannot be applied inside living cells, we present a viable strategy to improve the reactivity of gold catalysts in vivo.

Olefin metathesis catalysts like AquaMet are vulnerable to different decomposition pathways under biologically relevant conditions. Currently, stabilizing strategies are focused on approaches with limited relevance for application under biologically relevant conditions. Initial attempts to stabilise AquaMet by encapsulation within a supramolecular metallocage showed that the nitrate counterions of the cage improve the activity of the catalyst. We show that the chloride ligands of AquaMet can be replaced with nitrates by simple anion‐exchange. Catalytic studies into metathesis of a diallyl substrate showed that the presence of nitrate generates higher yields of the ring‐closed product compared to AquaMet alone, under aqueous and biological conditions. Kinetic studies support that the nitrate‐containing catalyst both initiates faster and performs catalysis at a much faster rate than AquaMet, while the rate of catalyst deactivation was similar. This new strategy of kinetic protection of a transition metal catalyst may have future applications for other catalytic reactions applied in vivo.

The importance of transition metal catalysis is exemplified by its wide range of applications, for example in the synthesis of chemicals, natural products, and pharmaceuticals. However, one relatively new application is for carrying out new‐to‐nature reactions inside living cells. The complex environment of a living cell is not welcoming to transition metal catalysts, as a diverse range of biological components have the potential to inhibit or deactivate the catalyst. Here we review the current progress in the field of transition metal catalysis, and evaluation of catalysis efficiency in living cells and under biological (relevant) conditions. Catalyst poisoning is a ubiquitous problem in this field, and we propose that future research into the development of physical and kinetic protection strategies may provide a route to improve the reactivity of catalysts in cells.