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

Abstract

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.

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

“…Phototoxicity of Ru complexes arises from two different mechanisms. One mechanism is singlet oxygen ( 1 O 2 ) sensitization using Ru complexes for photodynamic therapy (PDT) . The other mechanism is uncaging cytotoxic ligands or Ru species via ligand photosubstitution reactions for photoactivated chemotherapy (PACT) …”

Selective Preparation of a Heteroleptic Cyclometallated Ruthenium Complex Capable of Undergoing Photosubstitution of a Bidentate Ligand

“…Indeed,f or PACT,b identate ligandso ffer better caging in the dark than monodentate ligands. [25,26] For polypyridyl complexes such as [Ru(bpy) 2 (mtmp)] 2 + (bpy = 2,2'-bipyridine) or [Ru(Ph 2 phen) 2 (mtmp)] 2 + (Ph 2 phen = 4,7-diphenyl-1,10-phenanthroline), thioether-containing bidentate chelates such as 2-(methylthio)methylpyridine (mtmp)h ave recently been shown to be selectively photosubstituted by two water molecules upon irradiation with blue light in water. [27] Here, we first investigated whether mtmp and three analogues thereof, 3-(methylthio)propylamine (mtpa), 2-(methylthio)ethylamine (mtea), and 2-(methylthio)ethyl-2-pyridine (mtep), could be stereoselectively coordinated to cage the cyclometallated precursor [Ru(bpy)(phpy)(CH 3 CN) 2 ]PF 6 ([1a]PF 6 )a nd thereby prepare well-characterized heteroleptic complexes [Ru(bpy)(phpy)(N,S)]PF 6 ([2]PF 6 -[5]PF 6 )( Scheme 1).…”

“…In this work, we have sought to prepare cycloruthenated complexes capable of undergoing photosubstitution of a bidentate ligand. Indeed, for PACT, bidentate ligands offer better caging in the dark than monodentate ligands . For polypyridyl complexes such as [Ru(bpy) 2 (mtmp)] 2+ (bpy=2,2′‐bipyridine) or [Ru(Ph 2 phen) 2 (mtmp)] 2+ (Ph 2 phen=4,7‐diphenyl‐1,10‐phenanthroline), thioether‐containing bidentate chelates such as 2‐(methylthio)methylpyridine (mtmp) have recently been shown to be selectively photosubstituted by two water molecules upon irradiation with blue light in water .…”

Synthesis and Light-Induced Actuation of Photo-Labile 2-Pyridyl-1,2,3-Triazole Ru(bis-bipyridyl) Appended Ferrocene Rotors

“…The most commonly investigated metal ion for photo-induced ligand ejection is Ru(II), although examples involving osmium(II) complexes have been reported [ 36 ]. Photo-induced ligand-ejection from ruthenium(II), which is usually considered to form inert coordination bonds, has been recently studied for medicinal applications, with a number of reports developing prodrugs which undergo photo-ligand ejection, towards ‘switch-on cytotoxicity’ type technology to fight diseases such as cancer [ 37 , 38 , 39 , 40 , 41 , 42 ]. However, other potential applications have been investigated [ 43 ], including photo-induced self-assembly [ 44 ], and molecular motion [ 45 ].…”

“…However, other potential applications have been investigated [ 43 ], including photo-induced self-assembly [ 44 ], and molecular motion [ 45 ]. There are two main strategies used when designing bidentate ligands for the purpose of photo-ejection from [Ru(L) 2 ] 2+ (where L is a bidentate N–N donor ligand) type units: One is to create a sterically encumbered coordination environment, often by adding functionalities in the ortho positions of coordinating pyridyl donors [ 32 , 40 , 46 , 47 ]. The other is to simply create a ligand with weaker donor capability [ 48 ].…”