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.     

Luminescent zinc(ii) and copper(i) complexes for high-performance solution-processed monochromic and white organic light-emitting devices

The synthesis and spectroscopic properties of luminescent tetranuclear zinc(ii) complexes of substituted 7-azaindoles and a series of luminescent copper(i) complexes containing 7,8-bis(diphenylphosphino)-7,8-dicarba-nido-undecaborate ligand are described. These complexes are stable towards air and moisture. Thin film samples of the luminescent copper(i) complexes in 2,6-dicarbazolo-1,5-pyridine and zinc(ii) complexes in poly(methyl methacrylate) showed emission quantum yields of up to 0.60 (for Cu-3) and 0.96 (for Zn-1), respectively. Their photophysical properties were examined by ultrafast time-resolved emission spectroscopy, temperature dependent emission lifetime measurements and density functional theory calculations. Monochromic blue and orange solution-processed OLEDs with these Zn(ii) and Cu(i) complexes as light-emitting dopants have been fabricated, respectively. Maximum external quantum efficiency (EQE) of 5.55% and Commission Internationale de l''Eclairage (CIE) coordinates of (0.16, 0.19) were accomplished with the optimized Zn-1-OLED while these values were, respectively 15.64% and (0.48, 0.51) for the optimized Cu-3-OLED. Solution-processed white OLEDs having maximum EQE of 6.88%, CIE coordinates of (0.42, 0.44), and colour rendering index of 81 were fabricated by using these luminescent Zn(ii) and Cu(i) complexes as blue and orange light-emitting dopant materials, respectively.     

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.     

Operando X-ray absorption and EPR evidence for a single electron redox process in copper catalysis

An unprecedented single electron redox process in copper catalysis is confirmed using operando X-ray absorption and EPR spectroscopies. The oxidation state of the copper species in the interaction between Cu(ii) and a sulfinic acid at room temperature, and the accurate characterization of the formed Cu(i) are clearly shown using operando X-ray absorption and EPR evidence. Further investigation of anion effects on Cu(ii) discloses that bromine ions can dramatically increase the rate of the redox process. Moreover, it is proven that the sulfinic acids are converted into sulfonyl radicals, which can be trapped by 2-arylacrylic acids and various valuable β-keto sulfones are synthesized with good to excellent yields under mild conditions.     

AuICl-bound N-heterocyclic carbene ligands form MII4(LAuCl)6 integrally gilded cages

The incorporation of an N-heterocyclic carbene (NHC) moiety into a self-assembled MII4L₆ cage framework required the NHC first to be metallated with gold(i). Bimetallic cages could then be constructed using zinc(ii) and cadmium(ii) templates, showing weak luminescence. The cages were destroyed by the addition of further gold(i) in the form of Au^I(2,4,6-trimethoxybenzonitrile)₂SbF₆, which caused the reversibly-formed cages to disassemble and controllably release the Au^I-NHC subcomponent into solution. This release in turn induced the growth of gold nanoparticles. The rate of dianiline release could be tuned by capsule design or through the addition of chemical stimuli, with different release profiles giving rise to different nanoparticle morphologies.     

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.     

Encapsulation of Pt(iv) prodrugs within a Pt(ii) cage for drug delivery

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(iv) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(ii) cage that can host four Pt(iv) prodrug guest molecules. Relying on host–guest interactions between adamantyl units tethered to the Pt(iv) molecules and the cage, four prodrugs could be encapsulated within one cage. This host–guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host–guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(iv) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.     

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.     

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.     

Solid-phase synthesis provides a modular,lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols

We describe a modular, synthetically facile solid-phase approach aimed at separating the fluorescent reporter and binding unit of small-molecule metal-based sensors. The first representatives contain a lysine backbone functionalized with a tetramethylrhodamine fluorophore, and they operate by modulating the oxidation state of a copper ion ligated to an [N₄] (cyclam) or an [N₂O] (quinoline-phenolate) moiety. We demonstrate the selectivity of their Cu(ii) complexes for sensing nitroxyl (HNO) and thiols (RSH), respectively, and investigate the mechanism responsible for the observed reactivity in each case. The two lysine conjugates are cell permeable in the active, Cu(ii)-bound forms and retain their analyte selectivity intracellularly, even in the presence of interfering species such as nitric oxide, nitrosothiols, and hydrogen sulfide. Moreover, we apply the new probes to discriminate between distinct levels of intracellular HNO and RSH generated upon stimulation of live HeLa cells with ascorbate and hydrogen sulfide, respectively. The successful implementation of the lysine-based sensors to gain insight into biosynthetic pathways validates the method as a versatile tool for producing libraries of analogues with minimal synthetic effort.     

Concentration-dependent rhombitrihexagonal tiling patterns at the liquid/solid interface

We report STM investigations on a linear oligophenyleneethylene (OPE)-based self-assembling Pd(ii) complex 1 that forms highly-ordered concentration dependent patterns on HOPG. At high concentration, 2D lamellar structures are observed whereas the dilution of the system below a critical concentration leads to the formation of visually attractive rhombitrihexagonal Archimedean tiling arrangements featuring three different kinds of polygons: triangles, hexagons and rhombi. The key participation of the Cl ligands attached to the Pd(ii) centre in multiple C–H···Cl interactions was demonstrated by comparing the patterns of 1 with those of an analogous non-metallic system 2.     

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.     

Luminescent platinum(ii) complexes with self-assembly and anti-cancer properties: hydrogel,pH dependent emission color and sustained-release properties under physiological conditions

Supramolecular interactions are of paramount importance in biology and chemistry, and can be used to develop new vehicles for drug delivery. Recently, there is a surge of interest on self-assembled functional supramolecular structures driven by intermolecular metal–metal interactions in cellular conditions. Herein we report a series of luminescent Pt(ii) complexes [Pt(C^N^N^pyr)(CNR)]⁺ [HC^N^N^pyr = 2-phenyl-6-(1H-pyrazol-3-yl)-pyridine)] containing pincer type ligands having pyrazole moieties. These Pt(ii) complexes exert potent cytotoxicity to a panel of cancer cell lines including primary bladder cancer cells and display strong phosphorescence that is highly sensitive to the local environment. The self-assembly of these complexes is significantly affected by pH of the solution medium. Based on TEM, SEM, ESI-MS, absorption and emission spectroscopy, and fluorescence microscopy together with cell based assays, [Pt(C^N^N^pyr)(CNR)]⁺ complexes were observed to self-assemble into orange phosphorescent polymeric aggregates driven by intermolecular Pt(ii)–Pt(ii) and ligand–ligand interactions in a low-pH physiological medium. Importantly, the intracellular assembly and dis-assembly of [Pt(C^N^N^pyr)(CNR)]⁺ are accompanied by change of emission color from orange to green. These [Pt(C^N^N^pyr)(CNR)]⁺ complexes accumulated in the lysosomes of cancer cells, increased the lysosomal membrane permeability and induced cell death. One of these platinum(ii) complexes formed hydrogels which displayed pH-responsive and sustained release properties, leading to low-pH-stimulated and time-dependent cytotoxicity towards cancer cells. These hydrogels can function as vehicles to deliver anti-cancer agent cargo, such as the bioactive natural products studied in this work.     

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.     

Ruthenaelectro-catalyzed C–H acyloxylation for late-stage tyrosine and oligopeptide diversification

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of phenols have been developed by guidance of experimental, CV and computational insights. The use of electricity bypassed the need for stoichiometric chemical oxidants. The sustainable electrocatalysis strategy was characterized by ample scope, and its unique robustness enabled the late-stage C–H diversification of tyrosine-derived peptides.

Ruthenaelectro(ii/iv)-catalyzed intermolecular C–H acyloxylations of oligopeptides have been developed by the guidance of key experimental, CV and computational insights.     

Mixed valence mono- and hetero-metallic grid catenanes

Here, we report on the multicomponent self-assembly and single crystal X-ray diffraction study of a series of three interlocked mixed valence mono- and hetero-metallic [2]-catenanes made of [2 × 2] metallo-grids. They show unique structural features and highlight the essential roles of both the Cu(ii)/Cu(i) pair and of the conformationally adaptable organic ligands for achieving catenation of grids.     

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.     

Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors

Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(ii) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(ii) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC₅₀ ∼ 200 nM).     

The gold(i)···lead(ii) interaction: a relativistic connection

The crystal structure of complex [Pb{HB(pz)₃}Au(C₆Cl₅)₂] 1 displays an unsupported Au(i)···Pb(ii) interaction. This complex emits at 480 nm in the solid state due to an aurate(i) to lead(ii) charge transfer, in which the existence of a metallophilic interaction is a pre-requisite. Ab initio calculations show a very strong Au(i)···Pb(ii) closed-shell interaction of –390 kJ mol^–1, which has an ionic plus a dispersive (van der Waals) nature strengthened by large relativistic effects (>17%).