Ruthenium Polypyridyl Complexes Hopping at Anionic Lipid Bilayers through a Supramolecular Bond Sensitive to Visible Light

Abstract

The new ruthenium complex [Ru(terpy)(dcbpy)(Hmte)](PF(6))(2) ([2](PF(6))(2); dcbpy=6,6'-dichloro-2,2'-bipyridine, terpy=2,2';6',2"-terpyridine, Hmte=2-(methylthio)ethanol) was synthesized. In the crystal structure, this complex is highly distorted, revealing steric congestion between dcbpy and Hmte. In water, [2](2+) forms spontaneously by reacting Hmte and the aqua complex [Ru(terpy)(dcbpy)(OH(2))](2+) ([1](2+)), with a second-order rate constant of 0.025 s(-1) M(-1) at 25 °C. In the dark, the Ru-S bond of [2](2+) is thermally unstable and partially hydrolyzes; in fact, [1](2+) and [2](2+) are in an equilibrium characterized by an equilibrium constant K of 151 M(-1). When exposed to visible light, the Ru-S bond is selectively broken to release [1](2+), that is, the equilibrium is shifted by visible-light irradiation. The light-induced equilibrium shifts were repeated four times without major signs of degradation; the Ru-S coordination bond in [2](2+) can be described as a robust, light-sensitive, supramolecular bond in water. To demonstrate the potential of this system in supramolecular chemistry, a new thioether-cholesterol conjugate (4), which inserts into lipid bilayers through its cholesterol moiety and coordinates to ruthenium through its sulfur atom, was synthesized. Thioether-functionalized, anionic, dimyristoylphosphatidylglycerol (DMPG), lipid vesicles, to which aqua complex [1](2+) efficiently coordinates, were prepared. Upon exposure of the Ru-decorated vesicles to visible light, the Ru-S bond is selectively broken, thus releasing [1](2+) that stays at the water-bilayer interface. When the light is switched off, the metal complex spontaneously coordinates back to the membrane-embedded thioether ligands without a need to heat the system. This process was repeated four times at 35 °C, thus achieving light-triggered hopping of the metal complex at the water-bilayer interface.

Chemical Swarming: Depending on Concentration, an Amphiphilic Ruthenium Polypyridyl Complex Induces Cell Death via Two Different Mechanisms

“…The synthesis of all described ligands and complexes was performed as reported previously. 3β‐(2‐{2‐[2‐(Methylthio)ethoxy]ethoxy}ethoxy)cholesterol ( 2 ; CAS‐Nr: 1373125‐91‐7) was described by Bahreman et al . [Ru(tpy)(bpy)(Cl)]Cl and [ 1 ](PF 6 ) 2 were synthesized according to previous reports, and [ 3 ](PF 6 ) 2 was prepared as described by Askes et al .…”

Binding of a Ruthenium Complex to a Thioether Ligand Embedded in a Negatively Charged Lipid Bilayer: A Two‐Step Mechanism

“…Meanwhile, centrifugation experiments also showed that dicationic ruthenium aqua complexes interact significantly with negatively charged lipid bilayers even in the absence of thioether-cholesterol ligand. [34,35] These results suggested that adsorption of the bicationic ruthenium complexes to negatively charged bilayers may play a role in the mechanism of the coordination reaction of membrane-embedded sulfur ligands. However, it has up to now been impossible to detect such adsorption, notably because the changes occurring in the coordination sphere of the metal upon adsorption are not significant enough to allow detection by UV/Vis spectroscopy.…”

“…By dissolving [Ru(terpy)(dcbpy)(Cl)]Cl in an aqueous solution, the chloride ligand coordinated to ruthenium is quickly and quantitatively substituted by an aqua ligand to form [2] 2 + and two chloride anions. [35,36] Thus, replacing [2](PF 6 ) 2 by [Ru(terpy)(dcbpy)(Cl)]Cl allows for preparing 5 mm solutions of [2] 2 + with chloride counter anions instead of PF 6 À .…”

“…The thioether-cholesterol ligand 1 and the aqua ruthenium complex [2](PF 6 ) 2 were synthesized as reported previously. [35] 2-Dimyristoyl-sn-glycero-3-phosphoglycerol sodium salt (DMPG), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) sodium salt (DOPG) were obtained from Avanti Polar Lipids or Lipoid and stored at 253 K. Cholesterol, K 2 HPO 4 , K 2 HPO 4 , and K 2 SO 4 were obtained from commercial sources and used as received. A PerkinElmer Lambda 900 UV/Vis spectrometer equipped with stirring and temperature control was used for UV/ Vis measurements.…”

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

“…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.…”