Electrocatalytic Ammonia Oxidation with a Tailored Molecular Catalyst Heterogenized via Surface Host-Guest Complexation.

Macrocyclic host molecules bound to electrode surfaces enable the complexation of catalytically active guests for molecular heterogeneous catalysis. We present a surface-anchored host-guest complex with the ability to electrochemically oxidize ammonia in both organic and aqueous solutions. With an adamantyl motif as the binding group on the backbone of the molecular catalyst [Ru(bpy-NMe2)(tpada)(Cl)](PF6) (1) (where bpy-NMe2 is 4,4'-bis(dimethylamino)-2,2'-bipyridyl and tpada is 4'-(adamantan-1-yl)-2,2':6',2″-terpyridine), high binding constants with ß-cyclodextrin were observed in solution (in DMSO-d6:D2O (7:3), K11 = 492 ± 21 M-1). The strong binding affinities were also transferred to a mesoporous ITO (mITO) surface functionalized with a phosphonated derivative of ß-cyclodextrin. The newly designed catalyst (1) was compared to the previously reported naphthyl-substituted catalyst [Ru(bpy-NMe2)(tpnp)(Cl)](PF6) (2) (where tpnp is 4'-(naphthalene-2-yl)-2,2':6',2″-terpyridine) for its stability during catalysis. Despite the insulating nature of the adamantyl substituent serving as the binding group, the stronger binding of this unit to the host-functionalized electrode and the resulting shorter distance between the catalytic active center and the surface led to better performance and higher stability. Both guests are able to oxidize ammonia in both organic and aqueous solutions, and the host-anchored electrode can be refunctionalized multiple times (>3) following the loss of the catalytic activity, without a reduction in performance. Guest 1 exhibits significantly higher stability in comparison to guest 2 toward basic conditions, which often constitutes a challenge for anchored molecular systems. Ammonia oxidation in water led to the selective formation of NO3- with Faradaic efficiencies of up to 100%.

BODIPY-Based Photothermal Agents with Excellent Phototoxic Indices for Cancer Treatment.

Here, we report six novel, easily accessible BODIPY-based agents for cancer treatment. In contrast to established photodynamic therapy (PDT) agents, these BODIPY-based compounds show additional photothermal activity and their cytotoxicity is not dependent on the generation of reactive oxygen species (ROS). The agents show high photocytotoxicity upon irradiation with light and low dark toxicity in different cancer cell lines in 2D culture as well as in 3D multicellular tumor spheroids (MCTSs). The ratio of dark to light toxicity (phototoxic index, PI) of these agents reaches striking values exceeding 830,000 after irradiation with energetically low doses of light at 630 nm. The oxygen-dependent mechanism of action (MOA) of established photosensitizers (PSs) hampers effective clinical deployment of these agents. Under hypoxic conditions (0.2% O2), which are known to limit the efficiency of conventional PSs in solid tumors, photocytotoxicity was induced at the same concentration levels, indicating an oxygen-independent photothermal MOA. With a PI exceeding 360,000 under hypoxic conditions, both PI values are the highest reported to date. We anticipate that small molecule agents with a photothermal MOA, such as the BODIPY-based compounds reported in this work, may overcome this barrier and provide a new avenue to cancer therapy.

Azatriseptanes: Strained Framework Analogs of [7,7,7]Circulenes.

Invited for the cover of this issue is the group of Michel Rickhaus at the University of Zurich. The image depicts the "unearthing" of the highly contorted azatriseptane, a carbon framework consisting of three fused seven-membered rings surrounding a central nitrogen. Read the full text of the article at 10.1002/chem.202203954.

Azatriseptanes: Strained Framework Analogs of [7,7,7]Circulenes.

The synthesis and characterization of heptagon-embedded polycyclic aromatic compounds are essential for understanding the effect of negative curvature on carbon allotropes such as fullerenes and graphenes that have applications in functional organic materials. However, owing to the synthetic difficulties in functionalizing and embedding seven-membered rings, these strain-challenged structures are relatively unexplored. We report here the synthesis, characterization, and properties of a triarylamine core bridged with ethano chains at the 2,2'-positions. In doing so, we provide access to the first heterocycle containing three fused heptagon rings with a nitrogen at its core (BATA-NHAc). X-ray crystallographic analysis and DFT calculations revealed a remarkably strained structure wherein two of the bridged aryl units approach coplanarity, while the third ring is twisted out of plane at 70°. UV-vis and emission spectroscopies identify red-shifted absorption and concentration-dependent emission profiles, respectively, as a result of the unique conformation and self-assembly properties of BATA-NHAc. Furthermore, cyclic voltammetry shows a decrease in the oxidation potential for BATA-NHAc in comparison to the non-bridged analog. This study opens new avenues in understanding the structure-property relationships of curved π-aromatics and the construction of π-frameworks of increasing complexity.

Comparing PVP and Polymeric Micellar Formulations of a PEGylated Photosensitizing Phthalocyanine by NMR and Optical Techniques.

Phthalocyanines are ideal candidates as photosensitizers for photodynamic therapy (PDT) of cancer due to their favorable chemical and photophysical properties. However, their tendency to form aggregates in water reduces PDT efficacy and poses challenges in obtaining efficient forms of phthalocyanines for therapeutic applications. In the current work, polyvinylpyrrolidone (PVP) and micellar formulations were compared for encapsulating and monomerizing a water-soluble zinc phthalocyanine bearing four non-peripheral triethylene glycol chains (Pc1). 1H NMR spectroscopy combined with UV-vis absorption and fluorescence spectroscopy revealed that Pc1 exists as a mixture of regioisomers in monomeric form in dimethyl sulfoxide but forms dimers in an aqueous buffer. PVP, polyethylene glycol castor oil (Kolliphor RH40), and three different triblock copolymers with varying proportions of polyethylene and polypropylene glycol units (termed P188, P84, and F127) were tested as micellar carriers for Pc1. 1H NMR chemical shift analysis, diffusion-ordered spectroscopy, and 2D nuclear Overhauser enhancement spectroscopy was applied to monitor the encapsulation and localization of Pc1 at the polymer interface. Kolliphor RH40 and F127 micelles exhibited the highest affinity for encapsulating Pc1 in the micellar core and resulted in intense Pc1 fluorescence emission as well as efficient singlet oxygen formation along with PVP. Among the triblock copolymers, efficiency in binding and dimer dissolution decreased in the order F127 > P84 > P188. PVP was a strong binder for Pc1. However, Pc1 molecules are rather surface-attached and exist as monomer and dimer mixtures. The results demonstrate that NMR combined with optical spectroscopy offer powerful tools to assess parameters like drug binding, localization sites, and dynamic properties that play key roles in achieving high host-guest compatibility. With the corresponding adjustments, polymeric micelles can offer simple and easily accessible drug delivery systems optimizing phthalocyanines' properties as efficient photosensitizers.

Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase regulation in chronic kidney disease.

BACKGROUND: The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents have yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases. While prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase factor inhibiting HIF (FIH). METHODS: We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach to assess its relevance in CKD. RESULTS: In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with decreased development of fibrosis. CONCLUSIONS: The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease.

Binding Small Molecules to a cis-Dicarbonyl 99TcI-PNP Complex via Metal-Ligand Cooperativity.

Metal-ligand cooperativity is a powerful tool for the activation of various bonds but has rarely, if ever, been studied with the radioactive transition metal 99Tc. In this work, we explore this bond activation pathway with the dearomatized PNP complex cis-[99TcI(PyrPNPtBu*)(CO)2] (4), which was synthesized by deprotonation of trans-[99TcI(PyrPNPtBu)(CO)2Cl] with KOtBu. Analogous to its rhenium congener, the dearomatized compound reacts with CO2 to form the carboxy complex cis-[99TcI(PyrPNPtBu-COO)(CO)2] and with H2 to form the mono-hydride complex cis-[99TcI(PyrPNPtBu)(CO)2H] (7). Substrates with weakly acidic protons are deprotonated by the Brønsted basic pincer backbone of 4, yielding a variety of intriguing complexes. Reactions with terminal alkynes enable the isolation of acetylide complexes. The deprotonation of an imidazolium salt results in the in situ formation and coordination of a carbene ligand. Furthermore, a study with heterocyclic substrates allowed for the isolation of pyrrolide and pyrazolide complexes, which is uncommon for Tc. The spectroscopic analyses and their solid-state structures are reported.

An Iridium-Stabilized Borenium Intermediate.

Exploration of new organometallic systems based on polyhedral boron clusters has the potential to solve challenging chemical problems such as the stabilization of reactive intermediates and transition-state-like species postulated for E-H (E = H, B, C, Si) bond activation reactions. We report on facile and clean B-H activation of a hydroborane by a new iridium boron cluster complex. The product of this reaction is an unprecedented and fully characterized transition metal-stabilized boron cation or borenium. Moreover, this intermediate bears an unusual intramolecular B···H interaction between the hydrogen originating from the activated hydroborane and the cyclometallated metal-bonded boron atom of the boron cluster. This B···H interaction is proposed to be an arrested insertion of hydrogen into the Bcage-metal bond and the initiation step for iridium "cage-walking" around the upper surface of the boron cluster. The "cage-walking" process is supported by the hydrogen-deuterium exchange observed at the boron cluster, and a mechanism is proposed on the basis of theoretical methods with a special focus on the role of noncovalent interactions. All new compounds were isolated and fully characterized by NMR spectroscopy and elemental analysis. Key compounds were studied by single crystal X-ray diffraction and X-ray photoelectron spectroscopy.

Multitopic 3,2':6',3''-terpyridine ligands as 4-connecting nodes in two-dimensional 4,4-networks.

The tetratopic 1,4-bis(2-phenylethoxy)-2,5-bis(3,2':6',3''-terpyridin-4'-yl)benzene (1) and 1,4-bis(3-phenylpropoxy)-2,5-bis(3,2':6',3''-terpyridin-4'-yl)benzene (2) ligands have been prepared and fully characterised. Combination of ligand 1 or 2 and [M(hfacac)2]·xH2O (M = Cu, x = 1; M = Zn, x = 2) under conditions of crystal growth by layering led to the formation of [Cu2(hfacac)4(1)] n ·3.6n(1,2-Cl2C6H4)·2nCHCl3, [Zn2(hfacac)4(1)] n ·nMeC6H5·1.8nCHCl3, [Cu2(hfacac)4(2)] n ·nMeC6H5·2nH2O, [Cu2(hfacac)4(2)] n ·2.8nC6H5Cl and [Cu2(hfacac)4(2)] n ·2n(1,2-Cl2C6H4)·0.4nCHCl3·0.5nH2O. For each compound, single-crystal X-ray analysis revealed the assembly of a planar (4,4)-net in which the tetratopic ligands 1 or 2 define the nodes. The metal centres link two different bis(3,2':6',3''-tpy) ligands via the outer pyridine rings; whereas copper(ii) has N-donors in a trans-arrangement, zinc(ii) has them in cis. This difference between the copper(ii) and zinc(ii) coordination polymers modifies the architecture of the assembly without changing the underlying (4,4)-network.

Low-Dose Near-Infrared Light-Activated Mitochondria-Targeting Photosensitizers for PDT Cancer Therapy.

Phthalocyanines (Pcs) are promising candidates for photodynamic therapy (PDT) due to their absorption in the phototherapeutic window. However, the highly aromatic Pc core leads to undesired aggregation and decreased reactive oxygen species (ROS) production. Therefore, short PEG chain functionalized A3B type asymmetric Pc photosensitizers (PSs) were designed in order to decrease aggregation and increase the aqueous solubility. Here we report the synthesis, characterization, optical properties, cellular localization, and cytotoxicity of three novel Pc-based agents (LC31, MLC31, and DMLC31Pt). The stepwise functionalization of the peripheral moieties has a strong effect on the distribution coefficient (logP), cellular uptake, and localization, as well as photocytotoxicity. Additional experiments have revealed that the presence of the malonic ester moiety in the reported agent series is indispensable in order to induce photocytotoxicity. The best-performing agent, MLC31, showed mitochondrial targeting and an impressive phototoxic index (p.i.) of 748 in the cisplatin-resistant A2780/CP70 cell line, after a low-dose irradiation of 6.95 J/cm2. This is the result of a high photocytotoxicity (IC50 = 157 nM) upon irradiation with near-infrared (NIR) light, and virtually no toxicity in the dark (IC50 = 117 µM). Photocytotoxicity was subsequently determined under hypoxic conditions. Additionally, a preliminarily pathway investigation of the mitochondrial membrane potential (MMP) disruption and induction of apoptosis by MLC31 was carried out. Our results underline how agent design involving both hydrophilic and lipophilic peripheral groups may serve as an effective way to improve the PDT efficiency of highly aromatic PSs for NIR light-mediated cancer therapy.

Expanding the Cyclopentadienyl Framework: 99mTc/Re Complexes with Orthogonal Functions for Bioconjugation.

A series of bifunctional cyclopentadienes of the type 1,3-EtOCO-HCp-linker-NH2 were synthesized. In this series, the linker length (distance between the amine functionalities and the cyclopentadiene) has been systematically varied (CH2)n (n = 1-3). The corresponding Re complexes [(η5-C5H3RR')Re(CO)3] (R = -COOEt, R' = -linker-NH2) were synthesized and structurally characterized. They exhibit extraordinary stability toward water and air. All bifunctional cyclopentadienes have been labeled with the [99mTc(CO)3]+ moiety. Whereas the reactions with ethylene and propylene linked cyclopentadiene under mild reaction conditions led to the products in high radiochemical purity (>96%) without applying further purification protocols, harsher reaction conditions were required for the synthesis of the methylene-linked cyclopentadiene compound. Masking the amine in the methylene-linked cyclopentadiene by an amide bond bypasses this problem. The very hydrophilic characters of these complexes were assessed by KOW analysis. The reported cyclopentadienes and their complexes offer a robust and versatile platform for (radio)metal incorporation into biologically active lead structures.

Enantioselective Bifunctional Ammonium Salt-Catalyzed Syntheses of 3-CF3S-, 3-RS-, and 3-F-Substituted Isoindolinones.

We herein report the ammonium salt-catalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality in the 3-position. A broad variety of differently substituted CF3S- and RS-derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof-of-concept for the racemic synthesis of the analogous F-containing products was obtained as well, giving access to one of the rare examples of a fairly stable α-F-α-amino acid derivative.

Potent PBS/Polysorbate-Soluble Transplatin-Derived Porphyrin-Based Photosensitizers for Photodynamic Therapy.

In this study, we addressed an important drawback of our previously reported tetraplatinated (metallo)porphyrin-based photosensitizers (PSs) for photodynamic therapy (PDT), namely, the poor solubility in aqueous media. We aimed to create tetraplatinated porphyrin-based PSs that are soluble in aqueous media modified with polysorbate (Tween) and do not need to be pre-dissolved in organic solvents. A structural optimization of the previously reported PSs resulted in the synthesis of an extremely potent novel porphyrin-based PS. The novel PS displays effective phototoxicity upon light irradiation against multicellular tumor spheroids and has a phototoxic index (PI) of 6030 in HeLa cells. This PI value is, to the best of our knowledge, the highest value reported for any porphyrin so far.

Relativity as a Synthesis Design Principle: A Comparative Study of [3 + 2] Cycloaddition of Technetium(VII) and Rhenium(VII) Trioxo Complexes with Olefins.

The difference in [3 + 2] cycloaddition reactivity between fac-[MO3(tacn)]+ (M = Re, 99Tc; tacn = 1,4,7-triazacyclononane) complexes has been reexamined with a selection of unsaturated substrates including sodium 4-vinylbenzenesulfonate, norbornene, 2-butyne, and 2-methyl-3-butyn-2-ol (2MByOH). None of the substrates was found to react with the Re cation in water at room temperature, whereas the 99Tc reagent cleanly yielded the [3 + 2] cycloadducts. Interestingly, a bis-adduct was obtained as the sole product for 2MByOH, reflecting the high reactivity of a 99TcO-enediolato monoadduct. On the basis of scalar relativistic and nonrelativistic density functional theory calculations of the reaction pathways, the dramatic difference in reactivity between the two metals has now been substantially attributed to differences in relativistic effects, which are much larger for the 5d metal. Furthermore, scalar-relativistic ΔG values were found to decrease along the series propene > norbornene > 2-butyne > dimethylketene, indicating major variations in the thermodynamic driving force as a function of the unsaturated substrate. The suggestion is made that scalar-relativistic effects, consisting of greater destabilization of the valence electrons of the 5d elements compared with those of the 4d elements, be viewed as a new design principle for novel 99mTc/Re radiopharmaceuticals, as well as more generally in heavy-element coordination chemistry.

Exploring the Coordination Chemistry of N2 with Technetium PNP Pincer-Type Complexes.

Dinitrogen (N2) complexes of technetium (99Tc) are rare, and only two examples have been reported. To complement this important class of complexes also for 99Tc, two different pincer-type complexes of 99Tc were studied to assess their abilities for coordinating dinitrogen. The reactions of the 99TcIII complex [99TcCl3(PPh3)2(NCCH3)] with the pincer ligands PNPtBu and PyrPNPtBu respectively gave [99Tc(PNPtBu)Cl2] and [99Tc(PyrPNPtBu)Cl3], the first structurally characterized 99Tc complexes with mer-coordinated pincer ligands. Reductions with [Co(Cp*)2] under N2 gave the mononuclear bis-dinitrogen complex [99TcI(PNPtBu)(N2)2] and the dinuclear complex [99TcI(PyrPNPtBu)(N2)Cl]2(µ-N2) with both a bridging and a terminal N2 ligand. Spectroscopy and crystal structures confirm their identities. The complexes are stable under a dinitrogen atmosphere, and the N2 ligands are tightly bound. The results for the complexes with the PNPtBu pincer allow a comparison to its rhenium homologue, which has recently been shown to split the N2 ligand with the formation of a nitrido complex.

Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities.

The natural tripeptide glutathione (GSH) is a ubiquitous compound harboring various biological tasks, among them interacting with essential and toxic metal ions. Yet, although weakly binding the poisonous metal lead (Pb), GSH poorly detoxifies it. ß-Mercaptoaspartic acid is a new-to-nature novel amino acid that was found to enhance the Pb-detoxification capability of a synthetic cyclic tetrapeptide. Aiming to explore the advantages of noncanonical amino acids (ncAAs) of this nature, we studied the detoxification capabilities of GSH and three analogue peptides, each of which contains at least one ncAA that harbors both free carboxylate and thiolate groups. A thorough investigation that includes in vitro detoxification and mechanistic evaluations, metal-binding affinity, metal selectivity, and computational studies shows that these ncAAs are highly beneficial in additively enhancing Pb binding and reveals the importance of both high affinity and metal selectivity in synergistically reducing Pb toxicity in cells. Hence, such ncAAs join the chemical toolbox against Pb poisoning and pollution, enabling peptides to strongly and selectively bind the toxic metal ion.

New Crystalline Salts of Nicotinamide Riboside as Food Additives.

NR+ is a highly effective vitamin B3 type supplement due to its unique ability to replenish NAD+ levels. While NR+ chloride is already on the market as a nutritional supplement, its synthesis is challenging, expensive, and low yielding, making it cumbersome for large-scale industrial production. Here we report the novel crystalline NR+ salts, d/l/dl-hydrogen tartrate and d/l/dl-hydrogen malate. Their high-yielding, one-pot manufacture does not require specific equipment and is suitable for multi-ton scale production. These new NR+ salts seem ideal for nutritional applications due to their bio-equivalence compared to the approved NR+ chloride. In addition, the crystal structures of all stereoisomers of NR+ hydrogen tartrate and NR+ hydrogen malate and a comparison to the known NR+ halogenides are presented.

Cobalt Complexes of Polypyridyl Ligands for the Photocatalytic Hydrogen Evolution Reaction.

The reductive part of artificial photosynthesis, the reduction of protons into H2, is a two electron two proton process. It corresponds basically to the reactions occurring in natural photosystem I. We show in this review a selection of involved processes and components which are mandatory for making this light-driven reaction possible at all. The design and the performances of the water reduction catalysts is a main focus together with the question about electron relays or sacrificial electron donors. It is shown how an original catalyst is developed into better ones and what it needs to move from purely academic homogeneous processes to heterogeneous systems. The importance of detailed mechanistic knowledge obtained from kinetic data is emphasized.

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy.

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.

FeIII -Salen-Based Probes for the Selective and Sensitive Detection of E450 in Foodstuff.

Inorganic pyrophosphate (PPi) is considered as a diagnostic marker for various diseases such as cancer and vascular calcification. PPi also plays an important preservative role as an additive E450 in foodstuff. In this work, a selective FeIII -salen-based probe for PPi is described; this probe disassembles in the presence of the target analyte into its molecular blocks, 1,2-propanediamine and 3-chloro-5-formyl-4-hydroxybenzenesulfonic acid. The latter signaling unit leads to a fluorometric response. Compared with a related prototype, the new complex shows a 2.3-times stronger emission at 500 nm and a 155-times better selectivity of PPi over adenosine triphosphate (ATP). Importantly, the new probe was successfully applied for detecting E450 in foodstuff.