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

Abstract

The crystal structure and in vitro cytotoxicity of the amphiphilic ruthenium complex [3](PF6)2 are reported. Complex [3](PF6)2 contains a Ru−S bond that is stable in the dark in cell‐growing medium, but is photosensitive. Upon blue‐light irradiation, complex [3](PF6)2 releases the cholesterol–thioether ligand 2 and an aqua ruthenium complex [1](PF6)2. Although ligand 2 and complex [1](PF6)2 are by themselves not cytotoxic, complex [3](PF6)2 was unexpectedly found to be as cytotoxic as cisplatin in the dark, that is, with micromolar effective concentrations (EC50), against six human cancer cell lines (A375, A431, A549, MCF‐7, MDA‐MB‐231, and U87MG). Blue‐light irradiation (λ=450 nm, 6.3 J cm−2) had little influence on the cytotoxicity of [3](PF6)2 after 6 h of incubation time, but it increased the cytotoxicity of the complex by a factor 2 after longer (24 h) incubation. Exploring the unexpected biological activity of [3](PF6)2 in the dark elucidated an as‐yet unknown bifaceted mode of action that depended on concentration, and thus, on the aggregation state of the compound. At low concentration, it acts as a monomer, inserts into the membrane, and can deliver [1]2+ inside the cell upon blue‐light activation. At higher concentrations (>3–5 μm), complex [3](PF6)2 forms supramolecular aggregates that induce non‐apoptotic cell death by permeabilizing cell membranes and extracting lipids and membrane proteins.

Effects of the Bidentate Ligand on the Photophysical Properties, Cellular Uptake, and (Photo)cytotoxicity of Glycoconjugates Based on the [Ru(tpy)(NN)(L)]2+ Scaffold

“…The ligand photosubstitution was characterized by clear isosbestic points in the UV/Vis spectra (450 to 476 nm depending on the compound), as shown in Figure . For each of these reactions a bathochromic shift of the 1 MLCT band was observed, which is consistent with earlier reports on the formation of monoaqua‐ruthenium complexes in aqueous solution . Most complexes have a photosubstitution quantum yield ( Φ 450 ) of 0.5–2 percent, leading to photosubstitution reactivities ( ξ =Φ 450 < mx> ϵ 450, in which ϵ 450 is the molar absorption at 450 nm) on the order of ten to hundreds ( ξ =11–256).…”

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

“…Recently, the same group designed a photosensitive Ru(II) complex 14e . 245 The complex was found to have similar cytotoxicity as cisplatin in the dark and increased photocytoxicity after 24 h incubation with blue light activation. Interestingly, the complex had monomer characteristics at a low concentration (< 3.5 μM) and it released the monodentate ligand under blue light activation.…”

Synthesis and Avidin Binding of Ruthenium Complexes Functionalized with a Light‐Cleavable Free Biotin Moiety

“…We reported earlier on a method to cleave methionine‐ and biotin‐based ligands from a ruthenium(II) polypyridyl complex using visible light . Following the steps of Lo et al, Ward et al, and others, who showed that biotin‐tagged metal compounds could keep the biotin affinity for (strept)avidin, we embarked on investigating synthetically useful methods to functionalize photosubstitutionally active ruthenium polypyridyl complexes such as [Ru(tpy)(bpy)(Cl)]Cl with a free biotin fragment that can be removed by visible light, for future use in photochemotherapy , …”