A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

Lameijer, Lucien N.; Ernst, Daniël; Hopkins, Samantha L.; Meijer, Michael S.; Askes, Sven H. C.; Dévédec, Sylvia E. Le; Bonnet, Sylvestre

doi:10.1002/ange.201703890

Cited by 63 publications

(54 citation statements)

References 44 publications

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“…Ru(II) polypyridyl complexes are attractive systems for the development of light‐mediated biologically active compounds. Their photophysical and photochemical properties have been studied extensively over the years , and they have proven success as light‐responsive prodrugs for PDT and photochemotherapy (PCT) . The premise behind these phototherapies is that the initial metal complex serves as a relatively nontoxic compound that can be activated by light to become a powerful cytotoxin with high spatiotemporal selectivity for tumors.…”

Section: Introductionmentioning

confidence: 99%

“…In this work, we investigate a family of novel bis‐heteroleptic strained Ru(II) complexes for their potential to act as phototoxic agents in normoxia—but more importantly as PCT agents in hypoxia . We and others have an interest in developing systems that will be effective under these conditions, as most solid tumors contain hypoxic regions which are commonly resistant to radio‐ and chemotherapy. A key structural feature of the series is the modification of one organic ligand with different aromatic groups R (Chart ).…”

Section: Introductionmentioning

confidence: 99%

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Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Roque

Havrylyuk

Barrett

et al. 2019

Photochem & Photobiology

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A series of strained Ru(II) complexes were studied for potential anticancer activity in hypoxic tissues. The complexes were constructed with methylated ligands that were photolabile and an imidizo[4,5‐f][1,10]phenanthroline ligand that contained an appended aromatic group to potentially allow for contributions of ligand‐centered excited states. A systematic variation of the size and energy of the aromatic group was performed using systems containing 1–4 fused rings, and the photochemical and photobiological behaviors of all complexes were assessed. The structure and nature of the aromatic group had a subtle impact on photochemistry, altering environmental sensitivity, and had a significant impact on cellular cytotoxicity and photobiology. Up to 5‐fold differences in cytotoxicity were observed in the absence of light activation; this rose to 50‐fold differences upon exposure to 453 nm light. Most significantly, one complex retained activity under conditions with 1% O2, which is used to induce hypoxic changes. This system exhibited a photocytotoxicity index (PI) of 15, which is in marked contrast to most other Ru(II) complexes, including those designed for O2‐independent mechanisms of action.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Roque

Havrylyuk

Barrett

et al. 2019

Photochem & Photobiology

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“…12,33,49 The Ru(bpy) 2 fragment has also been used extensively to cage enzyme inhibitors and small-molecule drugs in live-cell assays. 21,28,34,36,50,51 Apart from Ru(bpy) 2 , Ru(II)-based photocaging groups are frequently composed of bi- or tridentate ancillary ligands, including 2,2′:6′,2″-terpyridine (tpy) and 1,10-phenanthroline (phen). 8,21,28,35,39,52,53 These imine-based photocages have been effectively applied to release bioactive molecules bearing nitriles, thioethers, and aromatic heterocycles, which generally cannot be protected by traditional organic photocages.…”

Section: Introductionmentioning

confidence: 99%

Ru(II) Polypyridyl Complexes Derived from Tetradentate Ancillary Ligands for Effective Photocaging

Turró

Kodanko

2018

Acc. Chem. Res.

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CONSPECTUS Metal complexes have many proven applications in the caging and photochemical release of biologically active compounds. Photocaging groups derived from Ru(II) traditionally have been composed of ancillary ligands that are planar and bi- or tridentate, such as 2,2′-bipyridine (bpy), 2,2′:6′,2″-terpyridine (tpy), and 1,10-phenanthroline (phen). Complexes bearing ancillary ligands with denticities higher than three represent a new class of Ru(II)-based photocaging groups that are grossly underdeveloped. Because high-denticity ancillary ligands provide the ability to increase the structural rigidity and control the stereochemistry, our groups initiated a research program to explore the applications of such ligands in Ru(II)-based photocaging. Ru(TPA), bearing the tetradentate ancillary ligand tris(2-pyridylmethyl)amine (TPA), has been successfully utilized to effectively cage nitriles and aromatic heterocycles. Nitriles and aromatic heterocycles caged by the Ru(TPA) group show excellent stability in aqueous solutions in the dark, and the complexes can selectively release the caged molecules upon irradiation with light. Ru(TPA) is applicable as a photochemical agent to offer precise spatiotemporal control over biological activity without undesired toxicity. In addition, Ru(II) polypyridyl complexes with desired photochemical properties can be synthesized and identified by solid-phase synthesis, and the resulting complexes show properties to similar to those of complexes obtained by solution-phase synthesis. Density functional theory (DFT) calculations reveal that orbital mixing between the π* orbitals of the ancillary ligand and the Ru−N dσ* orbital is essential for ligand photodissociation in these complexes. Furthermore, the introduction of steric bulk enhances the photoliability of the caged molecules, validating that steric effects can largely influence the quantum efficiency of photoinduced ligand exchange in Ru(II) polypyridyl complexes. Recently, two new photocaging groups, Ru(cyTPA) and Ru(1-isocyTPQA), have been designed and synthesized for caging of nitriles and aromatic heterocycles, and these complexes exhibit unique photochemical properties distinct from those derived from Ru(TPA). Notably, the unusually greater quantum efficiency for the ligand exchange in [Ru(1-isocyTPQA)(MeCN)2](PF6)2, Φ400 = 0.033(3), uncovers a trans-type effect in the triplet metal-to-ligand charge transfer (3MLCT) state that enhances photoinduced ligand exchange in a new manner. DFT calculations and ultrafast transient spectroscopy reveal that the lowest-energy triplet state in [Ru(1-isocyTPQA)(MeCN)2](PF6)2 is a highly mixed 3MLCT/3ππ* excited state rather than a triplet metal-centered ligand-field (3LF) excited state; the latter is generally accepted for ligand photodissociation. In addition, Mulliken spin density calculations indicate that a majority of the spin density in [Ru(1-isocyTPQA)(MeCN)2](PF6)2 is localized on the isoquinoline arm, which is opposite to the cis MeCN, rather than on the ruthenium center. This ...

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“…Their potential as selective and specific tools for biological research as well as agents for photoactivated chemotherapy (PACT) has been noted. 6–12 …”

Section: Introductionmentioning

confidence: 99%

“…24 The release of pyridine and other N-heterocycles is important due to the very large number of active agents available that contain these functional groups, opening the field of PACT to include compounds that can achieve a method of cell death independent of oxygen concentration, 12 unlike the case for photodynamic therapy, which requires oxygen. When the octahedral orientation is distorted using 6,6′-dimethyl-2,2′-bipyridine (Me 2 bpy), these complexes become more photo-reactive.…”

Section: Introductionmentioning

confidence: 99%

DFT Investigation of Ligand Photodissociation in [Ru^II(tpy)(bpy)(py)]²⁺ and [Ru^II(tpy)(Me₂bpy)(py)]²⁺ Complexes

Nisbett

Turró

et al. 2017

Inorg. Chem.

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Photoinduced ligand dissociation of pyridine occurs much more readily in [Ru(tpy)(Me2bpy)(py)]2+ than in [Ru(tpy)(bpy)(py)]2+ (tpy = 2,2′:6′,2″-terpyridine; bpy = 2,2′-bipyridine, Me2bpy = 6,6′-dimethyl-2,2′-bipyridine; py = pyridine). The S0 ground state and the 3MLCT and 3MC excited states of these complexes have been studied using BP86 density functional theory with the SDD basis set and effective core potential on Ru and the 6–31G(d) basis set for the rest of the atoms. In both complexes, excitation by visible light and intersystem crossing leads to a 3MLCT state in which an electron from a Ru d orbital has been promoted to a π* orbital of terpyridine, followed by pyridine release after internal conversion to a dissociative 3MC state. Interaction between the methyl groups and the other ligands causes significantly more strain in [Ru(tpy)(Me2bpy)(py)]2+ than in [Ru(tpy)(bpy)(py)]2+, in both the S0 and 3MLCT states. Transition to the dissociative 3MC states releases this strain, resulting in lower barriers for ligand dissociation from [Ru(tpy)(Me2bpy)(py)]2+ than from [Ru(tpy)(bpy)(py)]2+. Analysis of the molecular orbitals along relaxed scans for stretching the Ru–N bonds reveals that ligand photodissociation is promoted by orbital mixing between the ligand π* orbital of tpy in the 3MLCT state and the dσ* orbitals that characterize the dissociative 3MC states. Good overlap and strong mixing occur when the Ru–N bond of the leaving ligand is perpendicular to the π* orbital of terpyridine, favoring the release of pyridine positioned in a cis fashion to the terpyridine ligand.

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A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

Cited by 63 publications

References 44 publications

Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Ru(II) Polypyridyl Complexes Derived from Tetradentate Ancillary Ligands for Effective Photocaging

DFT Investigation of Ligand Photodissociation in [Ru^II(tpy)(bpy)(py)]²⁺ and [Ru^II(tpy)(Me₂bpy)(py)]²⁺ Complexes

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A Red‐Light‐Activated Ruthenium‐Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells

Cited by 63 publications

References 44 publications

Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Strained, Photoejecting Ru(II) Complexes that are Cytotoxic Under Hypoxic Conditions

Ru(II) Polypyridyl Complexes Derived from Tetradentate Ancillary Ligands for Effective Photocaging

DFT Investigation of Ligand Photodissociation in [RuII(tpy)(bpy)(py)]2+ and [RuII(tpy)(Me2bpy)(py)]2+ Complexes

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DFT Investigation of Ligand Photodissociation in [Ru^II(tpy)(bpy)(py)]²⁺ and [Ru^II(tpy)(Me₂bpy)(py)]²⁺ Complexes