Phototoxicity of strained Ru(<scp>ii</scp>) complexes: is it the metal complex or the dissociating ligand?

Azar, Daniel Fadi; Audi, Hassib; Farhat, Stephanie; El‐Sibai, Mirvat; Abi-Habib, Ralph J.; Khnayzer, Rony S.

doi:10.1039/c7dt02255g

Cited by 49 publications

(41 citation statements)

References 36 publications

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“…The half‐life (t 1/2 ) in water was found to be 4.3 min whereas it was 2.2 min in acetonitrile. As expected, t 1/2 in water was larger than in acetonitrile since the latter provides enhanced solvation of the photoproducts . However, it is important to note that the rate of photoejection is dependent on the concentration and volume of the solution as well as the incident power density.…”

Section: Resultssupporting

confidence: 55%

“…Results of cell viability assays showed that the toxicity of dmphen was significantly higher than the aqua complex formed and thus proved that the Ru II center can act as a cage for the cytotoxic ligand. These findings uncovered the important role of the coordinating ligands in the biological activity of strained Ru II polypyridyl complexes . Similarly, another report by Bonnet and co‐workers illustrated that the photoreleased 6,6′‐dimethyl‐2,2′‐bipyridine (dmbipy) ligand is responsible for the phototoxicity of [Ru(bipy) 2 (dmbipy)] 2+ , whereas the Ru bis‐aqua photoproduct was found to be biologically inert .…”

Section: Introductionmentioning

confidence: 69%

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Photoactivatable Ru^II Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

et al. 2018

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The current study investigates [Ru(bipy) 2 (dpphen)]-Cl 2 [where bipy = 2,2′-bipyridine and dpphen = 2,9-diphenyl-1,10-phenanthroline] (complex 1) for photoactivatable chemotherapy (PACT) application on five cancer cell lines.[Ru(bipy) 2 (phen)]Cl 2 [where phen = 1,10-phenanthroline] (complex 2) was included as an unstrained control. Upon excitation with visible light, complex 2 proved to be photostable while complex 1 underwent a quantitative dissociation of the bipy ligand and formation of a Ru II polypyridyl aqua complex in water. Complex 1 demonstrated only marginal activity in the dark; its cytotoxicity increased significantly upon photoactivation with a high phototoxicity index (PI = [IC 50 dark]/[IC 50 light]) [a]

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Section: Resultssupporting

confidence: 55%

Section: Introductionmentioning

confidence: 69%

Photoactivatable Ru^II Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

et al. 2018

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“…46, 47 The cytotoxicity of the strained, ejecting ligands for compounds 1 and 4 , 2 and 5 , and 7 were tested, and no cytotoxicity was observed at concentrations up to 30 μM. Accordingly, the activity of the complexes was attributed to the biological interactions of the Ru(II) fragment.…”

Section: Resultsmentioning

confidence: 99%

Photochemical and Photobiological Activity of Ru(II) Homoleptic and Heteroleptic Complexes Containing Methylated Bipyridyl-type Ligands

Kohler

Nease

et al. 2017

Inorg. Chem.

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Light activated compounds are powerful tools and potential agents for medical applications, as biological effects can be controlled in space and time. Ruthenium polypyridyl complexes can induce cytotoxic effects through multiple mechanisms, including acting as photosensitizers for singlet oxygen (1O2) production, the generation of other reactive oxygen species (ROS), the release of biologically active ligands, or through the creation of reactive intermediates that form covalent bonds to biological molecules. A structure activity relationship (SAR) study was performed on a series of Ru(II) complexes containing isomeric tetramethyl-substituted bipyridyl-type ligands. Three of the ligand systems studied contained strain-inducing methyl groups and created photolabile metal complexes, which can form covalent bonds to biomolecules upon light activation, while the fourth was unstrained and resulted in photostable complexes, which can generate 1O2. The compounds studied included both bis-heteroleptic complexes containing two bipyridine ligands and a third, substituted ligand, and tris-homoleptic complexes containing only the substituted ligand. The photophysics, electrochemistry, photochemistry, and photobiology were assessed. Strained heteroleptic complexes were found to be more photo-active and cytotoxic then tris-homoleptic complexes, and bipyridine ligands were superior to bipyrimidine. However, the homoleptic complexes exhibited an enhanced ability to inhibit protein production in live cells. Specific methylation patterns were associated with improved activation with red light, and photolabile complexes were generally more potent cytotoxic agents than the photostable 1O2 generating compounds.

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“…However, we and others demonstrated recently that the second photoproduct obtained upon irradiation of [Ru(bpy) 2 (dmbpy)] 2+ in water, i.e. the free dmbpy ligand, is the actual cytotoxic species [8,9]. These findings resulted in the formulation of two questions: first, can we design a lightactivated ruthenium complex in which the ruthenium bis-aqua photoproduct is the sole cytotoxic species?…”

Section: Introductionmentioning

confidence: 99%

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

Cuello-Garibo¹,

James²,

Siegler³

et al. 2017

Chem.Sq.

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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.

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Phototoxicity of strained Ru(ii) complexes: is it the metal complex or the dissociating ligand?

Cited by 49 publications

References 36 publications

Photoactivatable Ru^II Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

Photoactivatable Ru^II Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

Photochemical and Photobiological Activity of Ru(II) Homoleptic and Heteroleptic Complexes Containing Methylated Bipyridyl-type Ligands

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

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Phototoxicity of strained Ru(ii) complexes: is it the metal complex or the dissociating ligand?

Cited by 49 publications

References 36 publications

Photoactivatable RuII Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

Photoactivatable RuII Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

Photochemical and Photobiological Activity of Ru(II) Homoleptic and Heteroleptic Complexes Containing Methylated Bipyridyl-type Ligands

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

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Product

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Photoactivatable Ru^II Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines

Photoactivatable Ru^II Complex Bearing 2,9‐Diphenyl‐1,10‐phenanthroline: Unusual Photochemistry and Significant Potency on Cisplatin‐Resistant Cell Lines