How Ligand Geometry Affects the Reactivity of Co(II) Cyclam Complexes

Cobalt complexes are extensively studied as bioinspired models for non-heme oxygenases as they facilitate both the stabilization and characterization of metal-oxygen intermediates. As an analog to the well-known Co(cyclam) complex Co{N4} (cyclam=1,4,8,11-tetraazacyclotetradecane), the CoII complex Co{i-N4} with the isomeric isocyclam ligand (isocyclam=1,4,7,11-tetraazacyclotetradecane) was synthesized and characterized. Despite the identical N4 donor set of both complexes, Co{i-N4} enables the 2e−/2H+ reduction of O2 with a lower overpotential (ηeff of 385 mV vs. 540 mV for Co{N4}), albeit with a diminished turnover frequency. Characterization of the intermediates formed upon O2 activation of Co{i-N4} reveals a structurally identified stable μ-peroxo CoIII dimer as the main product. A superoxo CoIII species is also formed as a minor product, as indicated by EPR spectroscopy. In further reactivity studies, the electrophilicity of these in situ generated Co−O2 species was demonstrated by the oxidation of the O−H bond of TEMPO−H (2,2,6,6-tetramethylpiperidin-1-ol) via a H atom abstraction process. Unlike the known Co(cyclam), Co{i-N4} can be employed in oxygen atom transfer reactions oxidizing triphenylphosphine to the corresponding phosphine oxide highlighting the impact of geometrical modifications of the ligand while preserving the ring size and donor atom set on the reactivity of biomimetic oxygen activating complexes.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)Fraunhofer Internal ProgramsPeer Reviewe

A dithiacyclam-coordinated silver(i) polymer with anti-cancer stem cell activity

A cancer stem cell (CSC) active, solution stable, silver(i) polymeric complex bearing a dithiacyclam ligand is reported. The complex displays similar potency towards CSCs to salinomycin in monolayer and three-dimensional cultures. Mechanistic studies suggest CSC death results from cytosol entry, an increase in intracellular reactive oxygen species, and caspase-dependent apoptosis

Beweis von Schwefel‐non‐Innocence in [CoII(Dithiacyclam)]2+ ‐vermittelten, katalytischen Sauerstoff‐Reduktions‐Reaktionen

In vielen Metallenzymen sind Schwefel-enthaltende Liganden an Elektronen-Transfer-Reaktionen beteiligt. In dem hier diskutierten biomimetischen Ansatz wird der Einfluss einer Schwefelkoordination auf eine Kobalt-katalysierte Sauerstoff-Reduktionsreaktion (ORR) demonstriert. Ein Vergleich des ORR-Vermögens eines vierfach Stickstoff-koordinierten [Co(Cyclam]2+-Komplexes (1; Cyclam=1,5,8,11-Tetraaza-cyclotetradecan) und dessen Schwefel-Analogons [Co(S2N2-Cyclam)]2+ (2; S2N2-Cyclam=1,8-Dithia-5,11-diazacyclotetradecan) zeigt verbesserte katalytische Eigenschaften mit dem in die Ligandensphäre am Kobalt eingeführten Chalkogen. Isolierung und Charakterisierung der Intermediate, die sich im Zuge der Sauerstoffaktivierung an den Kobalt(II)-Zentren von 1 und 2 bilden, identifizieren eine Beteiligung des Schwefels am O2-Reduktionsprozess als entscheidenden Faktor für die verbesserten Eigenschaften von 2 bei der katalytischen ORR

A bioinspired redox-modulating copper(II)– macrocyclic complex bearing non-steroidal anti-inflammatory drugs with anti-cancer stem cell activity

Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from in vitro studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex 1 comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of 1 is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that 1 kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that 1 is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that 1 evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)–NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates

Beweis von Schwefel‐non‐Innocence in [CoII(Dithiacyclam)]2+‐vermittelten, katalytischen Sauerstoff‐Reduktions‐Reaktionen

In vielen Metallenzymen sind Schwefel-enthaltende Liganden an Elektronen-Transfer-Reaktionen beteiligt. In dem hier diskutierten biomimetischen Ansatz wird der Einfluss einer Schwefelkoordination auf eine Kobalt-katalysierte Sauerstoff-Reduktionsreaktion (ORR) demonstriert. Ein Vergleich des ORR-Vermögens eines vierfach Stickstoff-koordinierten [Co(Cyclam]2+-Komplexes (1; Cyclam=1,5,8,11-Tetraaza-cyclotetradecan) und dessen Schwefel-Analogons [Co(S2N2-Cyclam)]2+ (2; S2N2-Cyclam=1,8-Dithia-5,11-diazacyclotetradecan) zeigt verbesserte katalytische Eigenschaften mit dem in die Ligandensphäre am Kobalt eingeführten Chalkogen. Isolierung und Charakterisierung der Intermediate, die sich im Zuge der Sauerstoffaktivierung an den Kobalt(II)-Zentren von 1 und 2 bilden, identifizieren eine Beteiligung des Schwefels am O2-Reduktionsprozess als entscheidenden Faktor für die verbesserten Eigenschaften von 2 bei der katalytischen ORR.Peer Reviewe

Electrochemical CO2_2 and proton reduction by a Co(dithiacyclam) complex

While [Ni(cyclam)]$^{2+}$ and [Ni(dithiacyclam)]$^{2+}$ complexes were shown to be potent electrocatalysts for the CO$_2$ conversion, their respective Co complexes hitherto received only little attention. Herein, we report on the CoII complexes of the cyclam and dithiacyclam platform, describe their synthesis and reveal their rich solvent dependent coordination chemistry. We show that sulfur implementation into the cyclam moiety leads to a switch from a low spin CoII complex in [Co(cyclam)]$^{2+}$ to a high spin form in [Co(dithiacyclam)]$^{2+}$. Notably, while both complexes are capable to perform the reduction of CO$_2$ to CO, H$_2$ formation is generally preferred. Along this line, the complexes were shown to enable proton reduction from acetic acid. However, in comparison to [Co(cyclam)]$^{2+}$, the altered electronics make [Co(dithiacyclam)]$^{2+}$ complexes prone to deposit on the glassy carbon working electrode over time leading to an overall low faradaic efficiency for the reduction of protons or CO$_2$

Mechanistic implications for the Ni(I)-catalyzed Kumada cross-coupling reaction

Herein we report on the cross-coupling reaction of phenylmagnesium bromide with aryl halides using the well-defined tetrahedral Ni(I) complex, [(Triphos)$Ni^{I}Cl$] (Triphos = 1,1,1-tris(diphenylphosphinomethyl)ethane). In the presence of 0.5 mol % [(Triphos)$Ni^{I}$Cl], good to excellent yields (75–97%) of the respective coupling products within a reaction time of only 2.5 h at room temperature were achieved. Likewise, the tripodal Ni(II)complexes [($\kappa^{2}-Triphos)Ni^{II}Cl_{2}$] and [($\kappa^{3}-Triphos)Ni^{II}Cl$](X) (X = ClO$_4$, BF$_4$) were tested as potential pre-catalysts for the Kumada cross-coupling reaction. While the Ni(II) complexes also afford the coupling products in comparable yields, mechanistic investigations by UV/Vis and electron paramagnetic resonance (EPR) spectroscopy indicate a Ni(I) intermediate as the catalytically active species in the Kumada cross-coupling reaction. Based on experimental findings and density functional theory (DFT) calculations, a plausible Ni(I)-catalyzed reaction mechanism for the Kumada cross-coupling reaction is presented

A bioinspired redox-modulating copper(II)-macrocyclic complex bearing non-steroidal anti-inflammatory drugs with anti-cancer stem cell activity

Copper(II) coordination compounds have been investigated for their anticancer properties for decades, however, none have reached advanced human clinical trials. The poor translation of copper(II) complexes from $\textit {in vitro}$ studies to (pre)clinical studies can be attributed to their limited efficacy in animal models, which is largely associated with copper leaching and speciation (in biological fluids). Here we report a biologically stable copper(II) complex based on the active site of Type I Cu electron transport proteins. The copper(II) complex $\bf 1$ comprises of dithiacyclam (with soft and hard donor atoms) and two diclofenac units, a nonsteriodial anti-inflammatory drug (NSAID). Extensive biophysical and electrochemical studies show that the solid state structure of $\bf 1$ is preserved in solution and that it can access both copper(I) and copper(II) oxidation states without leaching copper or undergoing speciation (in the presence of a cellular reductant). Cell studies show that $\bf 1$ kills bulk breast cancer cells and highly resistant breast cancer stem cells (CSCs) at micromolar concentrations, and is significantly less toxic towards a panel of non-cancerous cells. Clinically relevant spheroid studies show that $\bf 1$ is able to inhibit breast CSC-enriched mammosphere formation to a similar extent as salinomycin, a gold standard anti-CSC agent. Mechanistic studies show that $\bf 1$ evokes breast CSC death by elevating intracellular reactive oxygen species (ROS) and inhibiting cyclooxygenase-2 (COX-2) activity. The former leads to the activation of stress pathways (JNK and p38), which culminates in caspase-dependent apoptosis. This study reinforces the therapeutic potential of copper(II)–NSAID complexes and provides a bioinspired route to develop stable, ROS-generating copper-based anti-CSC drug candidates