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

The crystal structure and in vitro cytotoxicity of the amphiphilic ruthenium complex [3](PF(6))(2) are reported. Complex [3](PF(6))(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](PF(6))(2) releases the cholesterol–thioether ligand 2 and an aqua ruthenium complex [1](PF(6))(2). Although ligand 2 and complex [1](PF(6))(2) are by themselves not cytotoxic, complex [3](PF(6))(2) was unexpectedly found to be as cytotoxic as cisplatin in the dark, that is, with micromolar effective concentrations (EC(50)), 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](PF(6))(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](PF(6))(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](PF(6))(2) forms supramolecular aggregates that induce non‐apoptotic cell death by permeabilizing cell membranes and extracting lipids and membrane proteins.