Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was "caged" by coordination of its thioether group to a photosensitive ruthenium complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell line monolayers, 3D lung cancer tumor spheroids (A549), and a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O 2 ) but also remarkably in hypoxic conditions (1% O 2 ). In vivo, low toxicity was observed at a dose of 1 mg•kg −1 when the compound was injected intraperitoneally, and light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the safety and efficacy of ruthenium-based photoactivated chemotherapy compounds in a tumor xenograft.

In this work, two new photopharmacological ruthenium prodrugs are described that can be activated by green light. Cell death occurs via apoptosis; it is not a consequence of singlet oxygen generation, but of light-induced photosubstitution reactions.

A number of nickel(II) dihalide complexes with small monodentate N-heterocyclic carbene ligands was synthesized and tested for their catalytic activity in the hydrosilylation of internal alkynes. The nickel(0) active species was obtained from the starting nickel(II) complex by reduction with diethylzinc. In all cases the catalytic reaction yielded the syn product selectively. The fastest catalysts reached full conversion

Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated L-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.

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.

Ruthenium polypyridyl complexes have received widespread attention as potential chemotherapeutics in photodynamic therapy (PDT) and in photochemotherapy (PACT). Here, we investigate a series of sixteen ruthenium polypyridyl complexes with general formula [Ru(tpy)(N−N)(L)]+/2+ (tpy=2,2′:6′,2′′‐terpyridine, N−N=bpy (2,2′‐bipyridine), phen (1,10‐phenanthroline), dpq (pyrazino[2,3‐f][1,10]phenanthroline), dppz (dipyrido[3,2‐a:2′,3′‐c]phenazine, dppn (benzo[i]dipyrido[3,2‐a:2′,3′‐c]phenazine), pmip (2‐(4‐methylphenyl)‐1H‐imidazo[4,5‐f][1,10]phenanthroline), pymi ((E)‐N‐phenyl‐1‐(pyridin‐2‐yl)methanimine), or azpy (2‐(phenylazo)pyridine), L=Cl− or 2‐(2‐(2‐(methylthio)ethoxy)ethoxy)ethyl‐β‐d‐glucopyranoside) and their potential for either PDT or PACT. We demonstrate that although increased lipophilicity is generally related to increased uptake of these complexes, it does not necessarily lead to increased (photo)cytotoxicity. However, the non‐toxic complexes are excellent candidates as PACT carriers.

The known ruthenium complex [Ru(tpy)(bpy)(Hmte)](PF6)2 ([1](PF6)2, where tpy = 2,2’:6’,2″-terpyridine, bpy = 2,2’-bipyridine, Hmte = 2-(methylthio)ethanol) is photosubstitutionally active but non-toxic to cancer cells even upon light irradiation. In this work, the two analogs complexes [Ru(tpy)(NN)(Hmte)](PF6)2, where NN = 3,3'-biisoquinoline (i-biq, [2](PF6)2) and di(isoquinolin-3-yl)amine (i-Hdiqa, [3](PF6)2), were synthesized and their photochemistry and phototoxicity evaluated to assess their suitability as photoactivated chemotherapy (PACT) agents. The increase of the aromatic surface of [2](PF6)2 and [3](PF6)2, compared to [1](PF6)2, leads to higher lipophilicity and higher cellular uptake for the former complexes. Such improved uptake is directly correlated to the cytotoxicity of these compounds in the dark: while [2](PF6)2 and [3](PF6)2 showed low EC50 values in human cancer cells, [1](PF6)2 is not cytotoxic due to poor cellular uptake. While stable in the dark, all complexes substituted the protecting thioether ligand upon light irradiation (520 nm), with the highest photosubstitution quantum yield found for [3](PF6)2 (Φ[3] = 0.070). Compounds [2](PF6)2 and [3](PF6)2 were found both more cytotoxic after light activation than in the dark, with a photo index of 4. Considering the very low singlet oxygen quantum yields of these compounds, and the lack of cytotoxicity of the photoreleased Hmte thioether ligand, it can be concluded that the toxicity observed after light activation is due to the photoreleased aqua complexes [Ru(tpy)(NN)(OH2)]2+, and thus that [2](PF6)2 and [3](PF6)2 are promising PACT candidates. Graphic abstract

Coupling the notoriously non-emissive complex [Ru(tpy)(bpy)Cl]Cl (tpy = 2,2':6',2''-terpyridine, bpy = 2,2'-bipyridine) to a C alkyl chain via an amide linker on the 4' position of the terpyridine yielded a new amphiphilic ruthenium complex showing red emission and chloride-dependent aggregation properties. This emissive complex is highly cytotoxic in A549 non-small lung cancer cells where it can be followed by confocal microscopy. Uptake occurs within minutes, first by insertion into the cellular membrane, and then by migration to the peri-nuclear region.