Combination of Ru(ii) complexes and light: new frontiers in cancer therapy

The synergistic action of light, oxygen and a photosensitizer (PS) has found applications for decades in medicine under the name of photodynamic therapy (PDT) for the treatment of skin diseases and, more recently, for the treatment of cancer. However, of the thirteen PSs currently approved for the treatment of cancer over more than 10 countries, only two contain a metal ion. This fact is rather surprising considering that nowadays around 50% of conventional chemotherapies involve the use of cisplatin and other platinum-containing drugs. In this perspective article, we review the opportunities brought by the use of Ru(ii) complexes as PSs in PDT. In addition, we also present the recent achievements in the application of Ru(ii) complexes in photoactivated chemotherapy (PACT). In this strategy, the presence of oxygen is not required to achieve cell toxicity. This is of significance since tumors are generally hypoxic. Importantly, this perspective article focuses particularly on the Ru(ii) complexes for which an in vitro biological evaluation has been performed and the mechanism of action (partially) unveiled.     

DFT insight into asymmetric alkyl–alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins

A DFT study has been conducted to understand the asymmetric alkyl–alkyl bond formation through nickel-catalysed reductive coupling of racemic alkyl bromide with olefin in the presence of hydrosilane and K₃PO₄. The key findings of the study include: (i) under the reductive experimental conditions, the Ni(ii) precursor is easily activated/reduced to Ni(0) species which can serve as an active species to start a Ni(0)/Ni(ii) catalytic cycle. (ii) Alternatively, the reaction may proceed via a Ni(i)/Ni(ii)/Ni(iii) catalytic cycle starting with a Ni(i) species such as Ni(i)–Br. The generation of a Ni(i) active species via comproportionation of Ni(ii) and Ni(0) species is highly unlikely, because the necessary Ni(0) species is strongly stabilized by olefin. Alternatively, a cage effect enabled generation of a Ni(i) active catalyst from the Ni(ii) species involved in the Ni(0)/Ni(ii) cycle was proposed to be a viable mechanism. (iii) In both catalytic cycles, K₃PO₄ greatly facilitates the hydrosilane hydride transfer for reducing olefin to an alkyl coupling partner. The reduction proceeds by converting a Ni–Br bond to a Ni–H bond via hydrosilane hydride transfer to a Ni–alkyl bond via olefin insertion. On the basis of two catalytic cycles, the origins for enantioconvergence and enantioselectivity control were discussed.

The enantioconvergent alkyl–alkyl coupling involves two competitive catalytic cycles with nickel(0) and nickel(i) active catalysts, respectively. K₃PO₄ plays a crucial role to enable the hydride transfer from hydrosilane to nickel–bromine species.     

Rationally designed Ru(ii)-metallacycle chemo-phototheranostic that emits beyond 1000 nm

Ruthenium complexes are emerging as potential complements to platinum drugs. They also show promise as photo-diagnostic and therapeutic agents. However, most ruthenium species studied to date as potential drugs are characterized by short excitation/emission wavelengths. This limits their applicability for deep-tissue fluorescence imaging and light-based therapeutic treatments. Here, we report a Ru(ii) metallacycle (Ru1100) that emits at ≥1000 nm. This system possesses excellent deep-tissue penetration capability (∼7 mm) and displays good chemo-phototherapeutic performance. In vitro studies revealed that Ru1100 benefits from good cellular uptake and produces a strong anticancer response against several cancer cell lines, including a cisplatin-resistant A549 cell line (IC₅₀ = 1.6 μM vs. 51.4 μM for cisplatin). On the basis of in vitro studies, it is concluded that Ru1100 exerts its anticancer action by regulating cell cycle progression and triggering cancer cell apoptosis. In vivo studies involving the use of a nanoparticle formulation served to confirm that Ru1100 allows for high-performance NIR-II fluorescence imaging-guided precise chemo-phototherapy in the case of A549 tumour mouse xenografts with no obvious side effects. This work thus provides a paradigm for the development of long-wavelength emissive supramolecular theranostic agents based on ruthenium.

Along-wavelength emissive Ru(ii) metallacycle chemo-phototheranostic was prepared via self-assembly that exhibits excellent photostability, deep-tissue penetration capability, and promising chemo-phototherapeutic performance in vitro and in vivo.     

Mg(ii) heterodinuclear catalysts delivering carbon dioxide derived multi-block polymers

Carbon dioxide derived polymers are emerging as useful materials for applications spanning packaging, construction, house-hold goods and automotive components. To accelerate and broaden their uptake requires both more active and selective catalysts and greater structural diversity for the carbon dioxide derived polymers. Here, highly active catalysts show controllable selectivity for the enchainment of mixtures of epoxide, anhydride, carbon dioxide and lactone. Firstly, metal dependent selectivity differences are uncovered using a series of dinuclear catalysts, Mg(ii)Mg(ii), Zn(ii)Zn(ii), Mg(ii)Zn(ii), and Mg(ii)Co(ii), each exposed to mixtures of bio-derived tricyclic anhydride, cyclohexene oxide and carbon dioxide (1 bar). Depending upon the metal combinations, different block structures are possible with Zn(ii)Zn(ii) yielding poly(ester-b-carbonate); Mg(ii)Mg(ii) or Mg(ii)Co(ii) catalysts delivering poly(carbonate-b-ester); and Mg(ii)Zn(ii) furnishing a random copolymer. These results indicate that carbon dioxide insertion reactions follow the order Co(ii) > Mg(ii) > Zn(ii). Using the most active and selective catalyst, Mg(ii)Co(ii), and exploiting reversible on/off switches between carbon dioxide/nitrogen at 1 bar delivers precision triblock (ABA), pentablock (BABAB) and heptablock (ABABABA) polymers (where A = poly(cyclohexylene oxide-alt-tricyclic anhydride), PE; B = poly(cyclohexene carbonate), PCHC). The Mg(ii)Co(ii) catalyst also selectively polymerizes a mixture of anhydride, carbon dioxide, cyclohexene oxide and ε-caprolactone to deliver a CBABC pentablock copolymer (A = PE, B = PCHC C = poly(caprolactone), PCL). The catalysts combine high activity and selectivity to deliver new polymers featuring regularly placed carbon dioxide and biomass derived linkages.

Carbon dioxide-based multiblock polymers are synthesised, in one-pot, from a mixture of monomers using a highly selective and active heterodinuclear Co(ii)Mg(ii) catalyst.     

Ferroptosis promotes sonodynamic therapy: a platinum(ii)–indocyanine sonosensitizer

Sonodynamic therapy (SDT) has unique advantages in deep tumour ablation due to its deep penetration depth, showing great preclinical and clinical potential. Herein, a platinum(ii)–cyanine complex has been designed to investigate its potential as a SDT anticancer agent. It generates singlet oxygen (¹O₂) under ultrasound (US) irradiation or light irradiation, and exhibits US-cytotoxicity in breast cancer 4T1 cells but with negligible dark-cytotoxicity. Mechanistic investigations reveal that Pt-Cy reduces the cellular GSH and GPX4, and triggers cancer cell ferroptosis under US irradiation. The metabolomics analysis illustrates that Pt-Cy upon US treatment significantly dysregulates glutathione metabolism, and finally induces ferroptosis. In vivo studies further demonstrate that Pt-Cy inhibits tumor growth under US irradiation and its efficiency for SDT is better than that for PDT in vivo. This is the first example of platinum(ii) complexes for sonodynamic therapy. This work extends the biological applications of metal complexes from PDT to SDT.

A novel platinum(ii)–cyanine complex showed a greater excellent sonodynamic therapeutic effect than photodynamic therapy in vivo. This work expands the biological applications of metal complexes from traditional photodynamic therapy to sonodynamic therapy.     

Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo

Oxaliplatin is a very potent platinum(ii) drug which is frequently used in poly-chemotherapy schemes against advanced colorectal cancer. However, its benefit is limited by severe adverse effects as well as resistance development. Based on their higher tolerability, platinum(iv) prodrugs came into focus of interest. However, comparable to their platinum(ii) counterparts they lack tumor specificity and are frequently prematurely activated in the blood circulation. With the aim to exploit the enhanced albumin consumption and accumulation in the malignant tissue, we have recently developed a new albumin-targeted prodrug, which supposed to release oxaliplatin in a highly tumor-specific manner. In more detail, we designed a platinum(iv) complex containing two maleimide moieties in the axial position (KP2156), which allows selective binding to the cysteine 34. In the present study, diverse cell biological and analytical tools such as laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), isotope labeling, and nano-scale secondary ion mass spectrometry (NanoSIMS) were employed to better understand the in vivo distribution and activation process of KP2156 (in comparison to free oxaliplatin and a non-albumin-binding succinimide analogue). KP2156 forms very stable albumin adducts in the bloodstream resulting in a superior pharmacological profile, such as distinctly prolonged terminal excretion half-life and enhanced effective platinum dose (measured by ICP-MS). The albumin-bound drug is accumulating in the malignant tissue, where it enters the cancer cells via clathrin- and caveolin-dependent endocytosis, and is activated by reduction to release oxaliplatin. This results in profound, long-lasting anticancer activity of KP2156 against CT26 colon cancer tumors in vivo based on cell cycle arrest and apoptotic cell death. Summarizing, albumin-binding of platinum(iv) complexes potently enhances the efficacy of oxaliplatin therapy and should be further developed towards clinical phase I trials.

Albumin-targeting of a maleimide-containing oxaliplatin-releasing platinum(iv) prodrug results in tumor-specific drug delivery and activity as shown by LA-ICP-MS, isotope-labeling and NanoSIMS in cell culture and in vivo.     

Photoredox catalysis via consecutive 2LMCT- and 3MLCT-excitation of an Fe(iii/ii)–N-heterocyclic carbene complex

Fe–N-heterocyclic carbene (NHC) complexes attract increasing attention as photosensitisers and photoredox catalysts. Such applications generally rely on sufficiently long excited state lifetimes and efficient bimolecular quenching, which leads to there being few examples of successful usage of Fe–NHC complexes to date. Here, we have employed [Fe(iii)(btz)₃]³⁺ (btz = (3,3′-dimethyl-1,1′-bis(p-tolyl)-4,4′-bis(1,2,3-triazol-5-ylidene))) in the addition of alkyl halides to alkenes and alkynes via visible light-mediated atom transfer radical addition (ATRA). Unlike other Fe–NHC complexes, [Fe(iii/ii)(btz)₃]^3+/2+ benefits from sizable charge transfer excited state lifetimes ≥0.1 ns in both oxidation states, and the Fe(iii) ²LMCT and Fe(ii) ³MLCT states are strong oxidants and reductants, respectively. The combined reactivity of both excited states enables efficient one-electron reduction of the alkyl halide substrate under green light irradiation. The two-photon mechanism proceeds via reductive quenching of the Fe(iii) ²LMCT state by a sacrificial electron donor and subsequent excitation of the Fe(ii) product to its highly reducing ³MLCT state. This route is shown to be more efficient than the alternative, where oxidative quenching of the less reducing Fe(iii) ²LMCT state by the alkyl halide drives the reaction, in the absence of a sacrificial electron donor.

An iron complex with N-heterocyclic carbene ligands engages in efficient photoredox catalysis via excited state electron transfer reactions of its Fe(ii) and Fe(iii) oxidation states.     

Dynamic supramolecular self-assembly of platinum(ii) complexes perturbs an autophagy–lysosomal system and triggers cancer cell death

Self-assembly of platinum(ii) complexes to form supramolecular structures/nanostructures due to intermolecular ligand π–π stacking and metal–ligand dispersive interactions is widely used to develop functional molecular materials, but the application of such non-covalent molecular interactions has scarcely been explored in medical science. Herein is described the unprecedented biological properties of platinum(ii) complexes relevant to induction of cancer cell death via manifesting such intermolecular interactions. With conjugation of a glucose moiety to the planar platinum(ii) terpyridyl scaffold, the water-soluble complex [Pt(tpy)(C CArOGlu)](CF₃SO₃) (1a, tpy = 2,2′:6′,2′′-terpyridine, Glu = glucose) is able to self-assemble into about 100 nm nanoparticles in physiological medium, be taken up by lung cancer cells via energy-dependent endocytosis, and eventually transform into other superstructures distributed in endosomal/lysosomal and mitochondrial compartments apparently following cleavage of the glycosidic linkage. Accompanying the formation of platinum-containing superstructures are increased autophagic vacuole formation, lysosomal membrane permeabilization, and mitochondrial membrane depolarization, as well as anti-tumor activity of 1a in a mouse xenograft model. These findings highlight the dynamic, multi-stage extracellular and intracellular supramolecular self-assembly of planar platinum(ii) complexes driven by modular intermolecular interactions with potential anti-cancer application.

Self-assembly of platinum(ii) glycosylated arylacetylide gave transformable superstructures upon enzymatic action in cellulo, leading to perturbation of an autophagy-lysosomal system and cancer cell death.     

Calcium ions tune the zinc-sequestering properties and antimicrobial activity of human S100A12

Human S100A12 is a host-defense protein expressed and released by neutrophils that contributes to innate immunity. Apo S100A12 is a 21 kDa antiparallel homodimer that harbors two Ca(ii)-binding EF-hand domains per subunit and exhibits two His₃Asp motifs for chelating transition metal ions at the homodimer interface. In this work, we present results from metal-binding studies and microbiology assays designed to ascertain whether Ca(ii) ions modulate the Zn(ii)-binding properties of S100A12 and further evaluate the antimicrobial properties of this protein. Our metal-depletion studies reveal that Ca(ii) ions enhance the ability of S100A12 to sequester Zn(ii) from microbial growth media. We report that human S100A12 has antifungal activity against Candida albicans, C. krusei, C. glabrata and C. tropicalis, all of which cause human disease. This antifungal activity is Ca(ii)-dependent and requires the His₃Asp metal-binding sites. We expand upon prior studies of the antibacterial activity of S100A12 and report Ca(ii)-dependent and strain-selective behavior. S100A12 exhibits in vitro growth inhibitory activity against Listeria monocytogenes. In contrast, S100A12 has negligible effect on the growth of Escherichia coli K-12 and Pseudomonas aeruginosa PAO1. Loss of functional ZnuABC, a high-affinity Zn(ii) import system, increases the susceptibility of E. coli and P. aeruginosa to S100A12, indicating that S100A12 deprives these mutant strains of Zn(ii). To evaluate the Zn(ii)-binding sites of S100A12 in solution, we present studies using Co(ii) as a spectroscopic probe and chromophoric small-molecule chelators in Zn(ii) competition titrations. We confirm that S100A12 binds Zn(ii) with a 2 : 1 stoichiometry, and our data indicate sub-nanomolar affinity binding. Taken together, these data support a model whereby S100A12 uses Ca(ii) ions to tune its Zn(ii)-chelating properties and antimicrobial activity.     

Aptamer-modified DNA tetrahedra-gated metal–organic framework nanoparticle carriers for enhanced chemotherapy or photodynamic therapy

UiO-66 metal–organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahedra provide superior biomarker-responsive hybrid nano-carriers for biomedical applications. Hybrid nano-carriers consisting of ATP-aptamer or VEGF-aptamer functionalized tetrahedra-gated NMOFs are loaded with the chemotherapeutic drug, doxorubicin (DOX). In the presence of ATP or VEGF, both abundant in cancer cells, the tetrahedra-gated NMOFs are unlocked to release the drug. Enhanced and selective permeation of the DOX-loaded ATP/VEGF-responsive tetrahedra-gated NMOFs into MDA-MB-231 breast cancer cells as compared to the reference ATP/VEGF-responsive duplex-gated NMOFs or non-malignant MCF-10A epithelial breast cells is observed. This results in enhanced and selective cytotoxicity of the tetrahedra-gated DOX-loaded NMOFs toward the malignant cells. Additional nano-carriers, consisting of photosensitizer Zn(ii) protoporphyrin IX (Zn(ii)-PPIX)-loaded VEGF-responsive tetrahedra-gated NMOFs, are introduced. The VEGF-triggered unlocking of the NMOFs yields separated G-quadruplex-VEGF aptamer complexes conjugated to the tetrahedra, resulting in the release of loaded Zn(ii)-PPIX. Association of the released Zn(ii)-PPIX to the G-quadruplex structures generates highly fluorescent supramolecular Zn(ii)-PPIX/G-quadruplex VEGF aptamer-tetrahedra structures. The efficient and selective generation of the highly fluorescent Zn(ii)-PPIX/G-quadruplex VEGF aptamer-tetrahedra nanostructures in malignant cells allows the light-induced photosensitized generation of reactive oxygen species (ROS), leading to high-efficacy PDT treatment of the malignant cells.

UiO-66 metal–organic framework nanoparticles (NMOFs) gated by aptamer-functionalized DNA tetrahedra provide superior biomarker-responsive hybrid nano-carriers for biomedical applications.     

Induction of targeted necrosis with HER2-targeted platinum(iv) anticancer prodrugs

It is well-recognized that the failure of many chemotherapeutics arises due to an inability to induce apoptosis. Most cancers acquire a myriad of pro-survival adaptations, and the vast heterogeneity and accumulation of multiple often unrelated anti-apoptotic signaling pathways have been a major stumbling block towards the development of conventional chemotherapeutics, which can overcome drug resistance. We have developed highly potent and selective HER2-targeted Pt(iv) prodrugs bearing anti-HER2/neu peptides that induce targeted necrosis as a novel strategy to circumvent apoptosis-resistance. These Pt(iv)–peptide conjugates exhibit a unique biphasic mode of cytotoxicity comprising rapid killing of cancer cells via necrosis in the first phase followed by an extended and gradual phase of delayed cell death. We demonstrate that these Pt(iv)–peptide prodrugs are more potent than their Pt(ii) congeners in direct cell-killing and exhibit comparable long-term inhibition of proliferative capacity and with greater selectivity against HER2-positive cancer cells.     

The switchable phosphorescence and delayed fluorescence of a new rhodamine-like dye through allenylidene formation in a cyclometallated platinum(ii) system

A new rhodamine-like alkyne-substituted ligand (Rhodyne) was designed to coordinate a cyclometallated platinum(ii) system. The chemo-induced “ON–OFF” switching capabilities on the spirolactone ring of the Rhodyne ligand with an end-capping platinum(ii) metal centre can modulate the interesting acetylide–allenylidene resonance. The long-lived ³IL excited state of Rhodyne in its ON state as an optically active opened form was revealed via steady-state and time-resolved spectroscopy studies. Exceptional near-infrared (NIR) phosphorescence and delayed fluorescence based on a rhodamine-like structure were observed at room temperature for the first time. The position of the alkyne communication bridge attached to the platinum(ii) unit was found to vary the lead(ii)-ion binding mode and also the possible resonance structure for metal-mediated allenylidene formation. The formation of a proposed allenylidene resonance structure was suggested to rationalize these phenomena.

A new rhodamine-like ligand (Rhodyne) was designed to coordinate a cyclometallated platinum(ii) system. Allenylidene formation could trigger NIR phosphorescence at 740 nm originating from Rhodyne ³IL, as well as delayed fluorescence at 620 nm.     

The mechanism of Fe induced bond stability of uranyl(v)

The stabilization of uranyl(v) (UO₂¹⁺) by Fe(ii) in natural systems remains an open question in uranium chemistry. Stabilization of U^VO₂¹⁺ by Fe(ii) against disproportionation was also demonstrated in molecular complexes. However, the relation between the Fe(ii) induced stability and the change of the bonding properties have not been elucidated up to date. We demonstrate that U(v) – oaxial bond covalency decreases upon binding to Fe(ii) inducing redirection of electron density from the U(v) – oaxial bond towards the U(v) – equatorial bonds thereby increasing bond covalency. Our results indicate that such increased covalent interaction of U(v) with the equatorial ligands resulting from iron binding lead to higher stability of uranyl(v). For the first time a combination of U M_4,5 high energy resolution X-ray absorption near edge structure (HR-XANES) and valence band resonant inelastic X-ray scattering (VB-RIXS) and ab initio multireference CASSCF and DFT based computations were applied to establish the electronic structure of iron-bound uranyl(v).

The role of Fe in the increased stability of uranyl(v) is clarified by using state of the art uranium metalorganic chemistry, advanced X-ray spectroscopic approaches and computations.     

Adaptive coordination assemblies based on a flexible tetraazacyclododecane ligand for promoting carbon dioxide fixation

Coordination hosts based on flexible ligands have received increasing attention due to their inherent adaptive cavities that often show induced-fit guest binding and catalysis like enzymes. Herein, we report the controlled self-assembly of a series of homo/heterometallic coordination hosts (Me₄enPd)_2n(ML)_n [n = 2/3; M = Zn(ii)/Co(ii)/Ni(ii)/Cu(ii)/Pd(ii)/Ag(i); Me₄en: N,N,N′,N′-tetramethylethylenediamine] with different shapes (tube/cage) from a flexible tetraazacyclododecane-based pyridinyl ligand (L) and cis-blocking Me₄enPd(ii) units. While the Ag(i)-metalated ligand (AgL) gave rise to the formation of a (Me₄enPd)₄(ML)₂-type cage, all other M(ii) ions led to isostructural (Me₄enPd)₆(ML)₃-type tubular complexes. Structural transformations between cages and tubes could be realized through transmetalation of the ligand. The buffering effect on the ML panels endows the coordination tubes with remarkable acid–base resistance, which makes the (Me₄enPd)₆(ZnL)₃ host an effective catalyst for the CO₂ to CO₃²⁻ conversion. Control experiments suggested that the integration of multiple active Zn(ii) sites on the tubular host and the perfect geometry match between CO₃²⁻ and the cavity synergistically promoted such a conversion. Our results provide an important strategy for the design of adaptive coordination hosts to achieve efficient carbon fixation.

A series of coordination hosts were prepared and their applications in CO₂ fixation were studied.     

Calcium-induced tetramerization and zinc chelation shield human calprotectin from degradation by host and bacterial extracellular proteases

Calprotectin (CP, S100A8/S100A9 oligomer, MRP-8/14 oligomer, calgranulins A and B) is a protein component of the innate immune system that contributes to the metal-withholding response by sequestering bioavailable transition metal ions at sites of infection. Human CP employs Ca(ii) ions to modulate its quaternary structure, transition metal binding properties, and antimicrobial activity. In this work, we report the discovery that Ca(ii)-induced self-association of human CP to afford heterotetramers protects the protein scaffold from degradation by host serine proteases. We present the design and characterization of two new human CP-Ser variants, S100A8(C42S)(I60E)/S100A9(C3S) and S100A8(C42S)(I60K)/S100A9(C3S), that exhibit defective tetramerization properties. Analytical size exclusion chromatography and analytical ultracentrifugation reveal that both variants, hereafter I60E and I60K, persist as heterodimers in the presence of Ca(ii) only, and form heterotetramers in the presence of Mn(ii) only and both Ca(ii) and Mn(ii). Coordination to Fe(ii) also causes I60E and I60K to form heterotetramers in both the absence and presence of Ca(ii). The Ca(ii)-bound I60E and I60K heterodimers are readily degraded by trypsin, chymotrypsin, and human neutrophil elastase, whereas the Ca(ii)-bound CP-Ser heterotetramers and the Ca(ii)- and Mn(ii)-bound I60E and I60K heterotetramers are resistant to degradation by these host proteases. The staphylococcal extracellular protease GluC cuts the S100A8 subunit of CP-Ser at the C-terminal end of residue 89 to afford a ΔSHKE variant. The GluC cleavage site is in close proximity to the His₃Asp metal-binding site, which coordinates Zn(ii) with high affinity, and Zn(ii) chelation protects the S100A8 subunit from GluC cleavage. Taken together, these results provide new insight into how Ca(ii) ions and transition metals modulate the chemistry and biology of CP, and indicate that coordination to divalent cations transforms human CP into a protease-resistant form and enables innate immune function in the hostile conditions of an infection site.     

Organocopper(ii) complexes: new catalysts for carbon–carbon bond formation via electrochemical atom transfer radical addition (eATRA)

Organocopper(ii) complexes are a rarity while organocopper(i) complexes are commonplace in chemical synthesis. In the course of building a strategy to generate organocopper(ii) species utilizing electrochemistry, a method to form compounds with Cu^II–C bonds was discovered, that demonstrated remarkably potent reactivity towards different functionalized alkenes under catalytic control. The role of the organocopper(ii) complex is to act as a source of masked radicals (in this case ˙CH₂CN) that react with an alkene to generate the corresponding γ-halonitrile in good yields through atom transfer radical addition (ATRA) to various alkenes. The organocopper(ii) complexes can be continuously regenerated electrochemically for ATRA (eATRA), which proceeds at room temperature, under low Cu loadings (1–10 mol%) and with the possibility of Cu-catalyst recovery.

Electrochemical generation of a novel organocopper(ii) complex offers a new way to carry out atom transfer radical addition to alkenes under mild conditions with high yields and low catalyst loadings.     

Kinetic trapping of a cobalt(ii) metallocage using a carbazole-containing expanded carbaporphyrinoid ligand

The meso-unsubstituted expanded porphyrinoid 3, incorporating two carbazole moieties, acts as an effective ligand for Co(ii) and permits the isolation and X-ray diffraction-based characterization of a 6 : 3 metal-to-ligand metallocage complex that converts spontaneously to the constituent 2 : 1 metal-to-ligand metalloring species in chloroform solution. The discrete metalloring is formed directly when the Co(ii) complex is crystallized from supersaturated solutions, whereas crystallization from more dilute solutions favors the metallocage. Studies with two other test cations, Pd(ii) and Zn(ii), revealed exclusive formation of the monomeric metalloring complexes with no evidence of higher order species being formed. Structural, electrochemical and UV-vis-NIR absorption spectral studies provide support for the conclusion that the Pd(ii) complex is less distorted and more effectively conjugated than its Co(ii) and Zn(ii) congeners, an inference further supported by TD-DFT calculations. The findings reported here underscore how expanded porphyrins can support coordination modes, including bimetallic complexes and self-assembled cage structures, that are not necessarily easy to access using more traditional ligand systems.

Carbazole containing expanded carbaporphyrinoid ligand supports the formation of 2 : 1 metal-to-ligand complexes with Pd, Co, and Zn. Solid-state studies also revealed formation of a 6 : 3 metal-to-ligand metallocage in the case of Co complexation.     

Photocytotoxicity and photoinduced phosphine ligand exchange in a Ru(ii) polypyridyl complex

Two new tris-heteroleptic Ru(ii) complexes with triphenylphosphine (PPh₃) coordination, cis-[Ru(phen)₂(PPh₃)(CH₃CN)]²⁺ (1a, phen = 1,10-phenanthroline) and cis-[Ru(biq)(phen)(PPh₃)(CH₃CN)]²⁺ (2a, biq = 2,2′-biquinoline), were synthesized and characterized for photochemotherapeutic applications. Upon absorption of visible light, 1a exchanges a CH₃CN ligand for a solvent water molecule. Surprisingly, the steady-state irradiation of 2a followed by electronic absorption and NMR spectroscopies reveals the photosubstitution of the PPh₃ ligand. Phosphine photoinduced ligand exchange with visible light from a Ru(ii) polypyridyl complex has not previously been reported, and calculations reveal that it results from a trans-type influence in the excited state. Complexes 1a and 2a are not toxic against the triple negative breast cancer cell line MDA-MB-231 in the dark, but upon irradiation with blue light, the activity of both complexes increases by factors of >4.2 and 5.8, respectively. Experiments with PPh₃ alone show that the phototoxicity observed for 2a does not arise from the released phosphine ligand, indicating the role of the photochemically generated ruthenium aqua complex on the biological activity. These complexes represent a new design motif for the selective release of PPh₃ and CH₃CN for use in photochemotherapy.

New Ru(ii) complexes exhibit selective ligand dissociation driven by an excited state trans-type influence. The complexes are not toxic to triple-negative breast cancer cells in the dark, but induce cell death upon irradiation with visible light.     

Controlling the optical and catalytic properties of artificial metalloenzyme photocatalysts using chemogenetic engineering

Visible light photocatalysis enables a broad range of organic transformations that proceed via single electron or energy transfer. Metal polypyridyl complexes are among the most commonly employed visible light photocatalysts. The photophysical properties of these complexes have been extensively studied and can be tuned by modifying the substituents on the pyridine ligands. On the other hand, ligand modifications that enable substrate binding to control reaction selectivity remain rare. Given the exquisite control that enzymes exert over electron and energy transfer processes in nature, we envisioned that artificial metalloenzymes (ArMs) created by incorporating Ru(ii) polypyridyl complexes into a suitable protein scaffold could provide a means to control photocatalyst properties. This study describes approaches to create covalent and non-covalent ArMs from a variety of Ru(ii) polypyridyl cofactors and a prolyl oligopeptidase scaffold. A panel of ArMs with enhanced photophysical properties were engineered, and the nature of the scaffold/cofactor interactions in these systems was investigated. These ArMs provided higher yields and rates than Ru(Bpy)₃²⁺ for the reductive cyclization of dienones and the [2 + 2] photocycloaddition between C-cinnamoyl imidazole and 4-methoxystyrene, suggesting that protein scaffolds could provide a means to improve the efficiency of visible light photocatalysts.

Artificial metalloenzyme visible light photocatalysts possess enhanced optical properties and are competent towards single electron and energy transfer organic transformations.     

Enhanced photoreduction of water catalyzed by a cucurbit[8]uril-secured platinum dimer

A cucurbit[8]uril (CB[8])-secured platinum terpyridyl chloride dimer was used as a photosensitizer and hydrogen-evolving catalyst for the photoreduction of water. Volumes of produced hydrogen were up to 25 and 6 times larger than those obtained with the corresponding free and cucurbit[7]uril-bound platinum monomer, respectively, at equal Pt concentration. The thermodynamics of the proton-coupled electron transfer from the Pt(ii)–Pt(ii) dimer to the corresponding Pt(ii)–Pt(iii)–H hydride key intermediate, as quantified by density functional theory, suggest that CB[8] secures the Pt(ii)–Pt(ii) dimer in a particularly reactive conformation that promotes hydrogen formation.

The cucurbit[8]uril macrocycle can secure a platinum terpyridyl complex into a particularly reactive dimer that catalyzes the photoreduction of water.