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.     

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.     

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.     

Design and recognition of cucurbituril-secured platinum-bound oligopeptides

Platinum terpyridyl complexes, stacked on top of one another and secured as dimers with cucurbit[8]uril (CB[8]) in aqueous medium, were functionalized quantitatively and in situ with a pair of pentapeptides Phe-(Gly)₃-Cys by grafting their cysteine residues to the Pt centers. The resulting CB[8]·(Pt·peptide)₂ assemblies were used to target secondary hosts CB[7] and CB[8] via their pair of phenylalanine residues, again in situ. A series of well-defined architectures, including a supramolecular “pendant necklace” with hybrid head-to-head and head-to-tail arrangements inside CB[8], were obtained during the self-sorting process after combining only 3 or 4 simple building units.

A platinum terpyridyl complex, pentapeptide Phe-(Gly)₃-Cys and cucurbit[8]uril assemble into a “pendant necklace” with hybrid head-to-head and head-to-tail arrangements in aqueous medium.     

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%).     

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.     

Self-assembly of a water-soluble endohedrally functionalized coordination cage including polar guests

Coordination cages containing endohedrally functionalized aromatic cavities are scarce in the literature. Herein, we report the self-assembly of a tetra-cationic super aryl-extended calix[4]pyrrole tetra-pyridyl ligand into a water-soluble Pd(ii)-cage featuring two endohedral polar binding sites. They are defined by the four pyrrole NHs of the calix[4]pyrrole unit and the four inwardly directed α-protons of the coordinated pyridyl groups. The efficient assembly of the Pd(ii)-cage requires the inclusion of mono- and ditopic pyridyl N-oxide and aliphatic formamide guests. The monotopic guests only partially fill the cage''s cavity and require the co-inclusion of a water molecule that is likely hydrogen-bonded to the endohedral α-pyridyl protons. The ditopic guests are able to completely fill the cage''s cavity and complement both binding sites. We observed high conformational selectivity in the inclusion of the isomers of α,ω-bis-formamides. We briefly investigate the uptake and release mechanism/kinetics of selected polar guests by the Pd(ii)-cage using pair-wise competition experiments.

A tetra-cationic calix[4]pyrrole tetra-pyridyl ligand self-assembles into a water-soluble Pd(ii)-cage featuring two endohedral polar binding sites. The Pd(ii)-cage encapsulates pyridyl N-oxide and aliphatic formamide guests in water.     

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.     

Platinum(ii) non-covalent crosslinkers for supramolecular DNA hydrogels

Manipulation of non-covalent metal–metal interactions allows the fabrication of functional metallosupramolecular structures with diverse supramolecular behaviors. The majority of reported studies are mostly designed and governed by thermodynamics, with very few examples of metallosupramolecular systems exhibiting intriguing kinetics. Here we report a serendipitous finding of platinum(ii) complexes serving as non-covalent crosslinkers for the fabrication of supramolecular DNA hydrogels. Upon mixing the alkynylplatinum(ii) terpyridine complex with double-stranded DNA in aqueous solution, the platinum(ii) complex molecules are found to first stack into columnar phases by metal–metal and π–π interactions, and then the columnar phases that carry multiple positive charges crosslink the negatively charged DNA strands to form supramolecular hydrogels with luminescence properties and excellent processability. Subsequent platinum(ii) intercalation into DNA competes with the metal–metal and π–π interactions at the crosslinking points, switching on the spontaneous gel-to-sol transition. In the case of a chloro (2,6-bis(benzimidazol-2′-yl)pyridine)platinum(ii) complex, with [Pt(bzimpy)Cl]⁺ serving as a non-covalent crosslinker where the metal–metal and π–π interactions outcompete platinum(ii) intercalation, the intercalation-driven gel-to-sol transition pathway is blocked since the gel state is energetically more favorable than the sol state. Interestingly, the ligand exchange reaction of the chloro ligand in [Pt(bzimpy)Cl]⁺ with glutathione (GSH) has endowed the complexes with enhanced hydrophilicity, decreasing the planarity of the complexes, and turning off the metal–metal and π–π interactions at the crosslinking points, leading to GSH-triggered hydrogel dissociation.

We report a serendipitous finding of platinum(ii) complexes serving as non-covalent crosslinkers for the fabrication of supramolecular DNA hydrogels.     

Ligand-field transition-induced C–S bond formation from nickelacycles

Photoexcitation is one of the acknowledged methods to activate Ni-based cross-coupling reactions, but factors that govern the photoactivity of organonickel complexes have not yet been established. Here we report the excited-state cross-coupling activities of Ni(ii) metallacycle compounds, which display ∼10⁴ times enhancement for the C–S bond-forming reductive elimination reaction upon Ni-centered ligand-field transitions. The effects of excitation energy and ancillary ligands on photoactivity have been investigated with 17 different nickelacycle species in combination with four corresponding acyclic complexes. Spectroscopic and computational electronic structural characterizations reveal that, regardless of coordinated species, d–d transitions can induce Ni–C bond homolysis, and that the reactivity of the resulting Ni(i) species determines the products of the overall reaction. The photoactivity mechanism established in this study provides general insights into the excited-state chemistry of organonickel(ii) complexes.

d–d excitations can accelerate C–S reductive eliminations of nickelacycles via intersystem crossing to a repulsive ³(C-to-Ni charge transfer) state inducing Ni–C bond homolysis. This homolytic photoreactivity is common for organonickel(ii) complexes.     

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.     

Ni(0)-promoted activation of Csp2–H and Csp2–O bonds

A dinickel(0)–N₂ complex, stabilized with a rigid acridane-based PNP pincer ligand, was studied for its ability to activate C(sp²)–H and C(sp²)–O bonds. Stabilized by a Ni–μ–N₂–Na⁺ interaction, it activates C–H bonds of unfunctionalized arenes, affording nickel–aryl and nickel–hydride products. Concomitantly, two sodium cations get reduced to Na(0), which was identified and quantified by several methods. Our experimental results, including product analysis and kinetic measurements, strongly suggest that this C(sp²)–H activation does not follow the typical oxidative addition mechanism occurring at a low-valent single metal centre. Instead, via a bimolecular pathway, two powerfully reducing nickel ions cooperatively activate an arene C–H bond and concomitantly reduce two Lewis acidic alkali metals under ambient conditions. As a novel synthetic protocol, nickel(ii)–aryl species were directly synthesized from nickel(ii) precursors in benzene or toluene with excess Na under ambient conditions. Furthermore, when the dinickel(0)–N₂ complex is accessed via reduction of the nickel(ii)–phenyl species, the resulting phenyl anion deprotonates a C–H bond of glyme or 15-crown-5 leading to C–O bond cleavage, which produces vinyl ether. The dinickel(0)–N₂ species then cleaves the C(sp²)–O bond of vinyl ether to produce a nickel(ii)–vinyl complex. These results may provide a new strategy for the activation of C–H and C–O bonds mediated by a low valent nickel ion supported by a structurally rigidified ligand scaffold.

A structurally rigidified nickel(0) complex was found to be capable of cleaving both C(sp²)–H and C(sp²)–O bonds.     

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.     

Stereoselective radical C–H alkylation with acceptor/acceptor-substituted diazo reagents via Co(ii)-based metalloradical catalysis

Co(ii)-based metalloradical catalysis has, for the first time, been successfully applied for asymmetric intramolecular C–H alkylation of acceptor/acceptor-substituted diazo reagents. Through the design and synthesis of a new D ₂-symmetric chiral amidoporphyrin as the supporting ligand, the Co(ii)-based metalloradical system, which operates at room temperature, is capable of 1,5-C–H alkylation of α-methoxycarbonyl-α-diazosulfones with a broad range of electronic properties, providing the 5-membered sulfolane derivatives in high yields with excellent diastereoselectivities and enantioselectivities. In addition to complete chemoselectivity toward allylic and allenic C–H bonds, the Co(ii)-based metalloradical catalysis for asymmetric C–H alkylation features a remarkable degree of functional group tolerance.     

A combined magnetic circular dichroism and density functional theory approach for the elucidation of electronic structure and bonding in three- and four-coordinate iron(ii)–N-heterocyclic carbene complexes

Iron salts and N-heterocyclic carbene (NHC) ligands is a highly effective combination in catalysis, with observed catalytic activities being highly dependent on the nature of the NHC ligand. Detailed spectroscopic and electronic structure studies have been performed on both three- and four-coordinate iron(ii)–NHC complexes using a combined magnetic circular dichroism (MCD) and density functional theory (DFT) approach that provide detailed insight into the relative ligation properties of NHCs compared to traditional phosphine and amine ligands as well as the effects of NHC backbone structural variations on iron(ii)–NHC bonding. Near-infrared MCD studies indicate that 10Dq(T _d) for (NHC)₂FeCl₂ complexes is intermediate between those for comparable amine and phosphine complexes, demonstrating that such iron(ii)–NHC and iron(ii)–phosphine complexes are not simply analogues of one another. Theoretical studies including charge decomposition analysis indicate that the NHC ligands are slightly stronger donor ligands than phosphines but also result in significant weakening of the Fe–Cl bonds compared to phosphine and amine ligands. The net result is significant differences in the d orbital energies in four-coordinate (NHC)₂FeCl₂ complexes relative to the comparable phosphine complexes, where such electronic structure differences are likely a significant contributing factor to the differing catalytic performances observed with these ligands. Furthermore, Mössbauer, MCD and DFT studies of the effects of NHC backbone structure variations (i.e. saturated, unsaturated, chlorinated) on iron–NHC bonding and electronic structure in both three- and four-coordinate iron(ii)–NHC complexes indicate only small differences as a function of backbone structure, that are likely amplified at lower oxidation states of iron due to the resulting decrease in the energy separation between the occupied iron d orbitals and the unoccupied NHC π* orbitals.     

Mixed lead–tin perovskite films with >7 μs charge carrier lifetimes realized by maltol post-treatment

Mixed lead–tin (Pb–Sn) halide perovskites with optimum band gaps near 1.3 eV are promising candidates for next-generation solar cells. However, the performance of solar cells fabricated with Pb–Sn perovskites is restricted by the facile oxidation of Sn(ii) to Sn(iv), which induces self-doping. Maltol, a naturally occurring flavor enhancer and strong metal binding agent, was found to effectively suppress Sn(iv) formation and passivate defects in mixed Pb–Sn perovskite films. When used in combination with Sn(iv) scavenging, the maltol surface treatment led to high-quality perovskite films which showed enhanced photoluminescence intensities and charge carrier lifetimes in excess of 7 μs. The scavenging and surface treatments resulted in highly reproducible solar cell devices, with photoconversion efficiencies of up to 21.4% under AM1.5G illumination.

Maltol, a metal binding agent, effectively passivates defects on the surface of mixed lead–tin perovskite films. The carrier lifetimes of the resultant perovskite films are over 7 μs. The solar cell devices exhibit efficiencies of up to 21.4%.     

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.     

Development of a panchromatic photosensitizer and its application to photocatalytic CO2 reduction

We designed and synthesized a heteroleptic osmium(ii) complex with two different tridentate ligands, Os. Os can absorb the full wavelength range of visible light owing to S–T transitions, and this was supported by TD-DFT calculations. Excitation of Os using visible light of any wavelength generates the same lowest triplet metal-to-ligand charge-transfer excited state, the lifetime of which is relatively long (τ_em = 40 ns). Since excited Os could be reductively quenched by 1,3-dimethyl-2-(o-hydroxyphenyl)-2,3-dihydro-1H-benzo[d]imidazole, Os displays high potential as a panchromatic photosensitizer. Using a combination of Os and a ruthenium(ii) catalyst, CO₂ was photocatalytically reduced to HCOOH via irradiation with 725 nm light, and the turnover number reached 81; irradiation with light at λ_ex > 770 nm also photocatalytically induced HCOOH formation. These results clearly indicate that Os can function as a panchromatic redox photosensitizer.

The osmium(ii) complex functioned as a panchromatic photosensitizer and drove CO₂ reduction.     

Kinetic resolution of sulfur-stereogenic sulfoximines by Pd(ii)–MPAA catalyzed C–H arylation and olefination

A direct Pd(ii)-catalyzed kinetic resolution of heteroaryl-enabled sulfoximines through an ortho-C–H alkenylation/arylation of arenes has been developed. The coordination of the sulfoximine pyridyl-motif and the chiral amino acid MPAA ligand to the Pd(ii)-catalyst controls the enantio-discriminating C(aryl)–H activation. This method provides access to a wide range of enantiomerically enriched unreacted aryl-pyridyl-sulfoximine precursors and C(aryl)–H alkenylation/arylation products in good yields with high enantioselectivity (up to >99% ee), and selectivity factor up to >200. The coordination preference of the directing group, ligand effect, geometry constraints, and the transient six-membered concerted-metalation–deprotonation species dictate the stereoselectivity; DFT studies validate this hypothesis.

A Pd/MPAA catalysed KR of heteroaryl substituted sulfoximines through C–H alkenylation and arylation (up to >99% ee) is developed. In-depth DFT studies uncover the salient features.