Synthesis, characterization, and biomedical evaluation of ethylene-bridged tetra-NHC Pd(ii), Pt(ii) and Au(iii) complexes, with apoptosis-inducing properties in cisplatin-resistant neuroblastoma cells.

Synthesis and characterization of the first two cyclic ethylene-bridged tetradentate NHC ligands, with an unsaturated (imidazole) and saturated backbone (2-imidazoline), are described. Complexes of both ligands containing palladium(ii) have been obtained. For platinum(ii) and gold(iii), only the unsaturated tetracarbene complexes could be isolated. The attempts to synthesize a methylene-bridged 2-imidazoline macrocycle are also described. Furthermore, a novel bisimidazolinium ligand precursor and its open-chain PdII and PtII tetracarbene complexes are obtained. Finally, it is shown that the unsaturated gold(iii) tetracarbene is able to induce apoptosis in malignant SK-N-AS neuroblastoma cells via the mitochondrial and ROS pathway and overcomes resistance to cisplatin in vitro.

Multi-site isomerization of synergistically regulated stimuli-responsive AIE materials toward multi-level decryption.

Stimuli-responsive aggregation-induced emission (AIE) materials are highly sensitive and rapidly responsive to external signals, making them ideal solid materials for anti-counterfeiting encryption. However, the limited conformational and packing variations resulting from regio-isomerization with a single substituent restricts the stimuli-responsive behavior of these materials. In this work, several AIE-active regio-structural isomers based on the salicylaldehyde Schiff base scaffold have been straightforwardly obtained through multiple substitutions with bromide and triphenylamine moieties. Solvent-effect experiments demonstrate their different orders of charge-transfer and excited-state intramolecular proton transfer upon photoexcitation, indicating the regulation of excited-state processes via multi-site isomerization. These isomers also demonstrate mechanochromism and acidichromism, allowing for adjustable stimuli-responsive effects. As a demonstration, p-Br-TPA with both mechanochromism and acidichromism can be synergistically utilized for multi-level decryption. This study successfully regulates the evolution of excited states through multi-site isomerization, offering a general approach for achieving tunable stimuli-responsive properties in AIE-active salicylaldehyde Schiff bases toward multi-level decryption.

Visible Light-Induced Regioselective Intermolecular [2 + 2]-Cycloaddition of Alkyne and 2(1H)-Quinolone Derivatives.

We have developed a visible light-induced intermolecular [2 + 2]-cycloaddition reaction between alkenes and alkynes using thioxanthone and Cu(OTf)2 as cocatalysts. Various quinolin-2(1H)-ones, featuring diverse substituted groups, were successfully employed in this reaction, resulting in the synthesis of a series of 4,8b-dihydrocyclobuta[c]quinolin-3(2aH)-ones. Our methodology presents a novel synthetic approach for alkene-alkyne [2 + 2]-cycloaddition, delivering cyclobutene derivatives with exceptional regioselectivity.

Recyclable N-Heterocyclic Carbene Porous Coordination Polymers with Two Distinct Metal Sites for Transformation of CO2 to Cyclic Carbonates.

Single-component catalysts with integrated multiple reactive centers could work in concert to achieve enhanced activity tailored for specific catalytic reactions, but they remain underdeveloped. Herein, we report the construction of heterogeneous bimetallic porous coordination polymers (PCPs) containing both porphyrin and N-heterocyclic carbene (NHC) metal sites via the coordinative assembly of the NHC functionalities. Three heterobimetallic PCPs (TIPP-Zn-Pd, TIPP-Cu-Pd and TIPP-Ni-Pd) have been prepared to verify this facile synthetic strategy for the first time. In order to establish a cooperative action toward the catalytic CO2 cycloaddition with epoxides, an additional tetraalkylammonium bromide functionality has also been incorporated into these polymeric structures through the N-substituent of the NHC moieties. The resulting heterogeneous bimetallic catalyst TIPP-Zn-Pd exhibits the best catalytic performance in CO2 cycloaddition with styrene oxide (SO) under solvent-free conditions at atmospheric pressure and is applicable to a wide range of epoxides. More importantly, TIPP-Zn-Pd works smoothly and is recyclable in the absence of a cocatalyst under 1.0 MPa of CO2 at 60 °C. This indicates that TIPP-Zn-Pd is quite competitive with the reported heterogeneous catalysts, which typically require a high reaction temperature above 100 °C under cocatalyst-free conditions. Thus, this work provides a new approach to design heterogeneous bimetallic PCP catalysts for high-performance CO2 fixation under mild reaction conditions.

Sustainable production of triazoles from lignin major motifs.

An efficiently catalyzed synthesis of pharmaceutically relevant 1,2,3-trazoles from renewable resources is highly desirable. However, due to incompatible catalysis conditions, this endeavor remained challenging so far. Herein, a practical access protocol to 1,2,3-triazoles, starting from lignin phenolic ß-O-4 with γ-OH group utilizing a vanadium-based catalyst is presented. A broad substrate scope reaching up to 97 % yield of 1,2,3-triazoles are obtained. The reaction pathway includes selective cleavage of double C-O bonds, cycloaddition, and dehydrogenation. Mechanistic studies and density-functional theory (DFT) calculations suggest that the V-based complex acts as a bifunctional catalyst for both selective C-O bonds cleavage and dehydrogenation. This synthetic pathway has been applied for the synthesis of pharmacological and biological active carbohydrate derivatives starting from biomass components as feedstock, enabling a potential sustainable route to triazolyl carbohydrate derivatives, which paves the way for lignin-based heterocyclic aromatics in the pharmaceutical applications.

Natural Acceptor of Coumarin-Isomerized Red-Emissive BioAIEgen for Monitoring Cu2+ Concentration in Live Cells via FLIM.

Artificial aggregation-induced emission luminogens (AIEgens) have flourished in bio-applications with the development of synthetic chemistry, which however are plagued by issues like singularity in structures and non-renewability. The unique structures and renewability of biomass moieties can compensate for these drawbacks, but their properties are hard to design and regulate due to their confined structures. Therefore, it appears to be a reasonable approach to derive AIEgens from abundant biomass (BioAIEgens), integrating the bilateral advantages of both synthetic and natural AIEgens. In this work, the blue-violet emissive coumarin with its lactone structure serving as a rare natural acceptor, is utilized to construct donor-π-acceptor typed BioAIE isomers incorporating the propeller-like and electron-donating triphenylamine (TPA) unit. The results show that Cm-p-TPA undergoes charge transfer with its keto form, emitting red light at 600 nm, which can be applied to monitor Cu2+ concentration during mitophagy using fluorescence lifetime imaging microscopy because of the excellent biocompatibility, photostability, and specific recognition to Cu2+ . This work not only demonstrates the feasibility of utilizing positional isomerization to modulate excited-state evolutions and resultant optical properties, but also provides evidence for the rationality of constructing biologically-active BioAIEgens via a biomass-derivatization concept.

Exploiting click-chemistry: backbone post-functionalisation of homoleptic gold(I) 1,2,3-triazole-5-ylidene complexes.

The synthesis of a homoleptic azide-functionalised Au(I) bis-1,2,3-triazole-5-ylidene complex is reported, starting from a backbone-modified 1,2,3-triazolium salt ligand precursor. The incorporated azide handle allows for a straightforward modification of the complex according to click-chemistry protocols without impacting the steric shielding around the metal center, demonstrating the superiority of the presented triazole ligand framework over imidazole based systems. Employing the SPAAC and the CuAAC reactions, post-modification of the complex is facilitated with two model substrates, while retaining very high antiproliferative activity (nanomolar range IC50 values) in A2780 and MCF-7 human cancer cells.

Towards bioresource-based aggregation-induced emission luminogens from lignin ß-O-4 motifs as renewable resources.

One-pot synthesis of heterocyclic aromatics with good optical properties from phenolic ß-O-4 lignin segments is of high importance to meet high value added biorefinery demands. However, executing this process remains a huge challenge due to the incompatible reaction conditions of the depolymerization of lignin ß-O-4 segments containing γ-OH functionalities and bioresource-based aggregation-induced emission luminogens (BioAIEgens) formation with the desired properties. In this work, benzannulation reactions starting from lignin ß-O-4 moieties with 3-alkenylated indoles catalyzed by vanadium-based complexes have been successfully developed, affording a wide range of functionalized carbazoles with up to 92% yield. Experiments and density functional theory calculations suggest that the reaction pathway involves the selective cleavage of double C-O bonds/Diels-Alder cycloaddition/dehydrogenative aromatization. Photophysical investigations show that these carbazole products represent a class of BioAIEgens with twisted intramolecular charge transfer. Distinctions of emission behavior were revealed based on unique acceptor-donor-acceptor-type molecular conformations as well as molecular packings. This work features lignin ß-O-4 motifs with γ-OH functionalities as renewable substrates, without the need to apply external oxidant/reductant systems. Here, we show a concise and sustainable route to functional carbazoles with AIE properties, building a bridge between lignin and BioAIE materials.

Cyclic iron tetra N-heterocyclic carbenes: synthesis, properties, reactivity, and catalysis.

Cyclic iron tetracarbenes are an emerging class of macrocyclic iron N-heterocyclic carbene (NHC) complexes. They can be considered as an organometallic compound class inspired by their heme analogs, however, their electronic properties differ, e.g. due to the very strong σ-donation of the four combined NHCs in equatorial coordination. The ligand framework of iron tetracarbenes can be readily modified, allowing fine-tuning of the structural and electronic properties of the complexes. The properties of iron tetracarbene complexes are discussed quantitatively and correlations are established. The electronic nature of the tetracarbene ligand allows the isolation of uncommon iron(III) and iron(IV) species and reveals a unique reactivity. Iron tetracarbenes are successfully applied in C-H activation, CO2 reduction, aziridination and epoxidation catalysis and mechanisms as well as decomposition pathways are described. This review will help researchers evaluate the structural and electronic properties of their complexes and target their catalyst properties through ligand design.

The first macrocyclic abnormally coordinating tetra-1,2,3-triazole-5-ylidene iron complex: a promising candidate for olefin epoxidation.

The first macrocyclic and abnormally coordinating, mesoionic N-heterocyclic carbene iron complex has been synthesised and characterised via ESI-MS, EA, SC-XRD, CV, NMR and UV/Vis spectroscopy. 13C-NMR spectroscopy and CV measurements indicate a strong σ-donor ability of the carbene moieties, suggesting an efficient catalytic activity of the iron complex in oxidation reactions. Initial tests in the epoxidation of cis-cyclooctene as a model substrate confirm this assumption.

Transition-Metal-Free Synthesis of Functionalized Quinolines by Direct Conversion of ß-O-4 Model Compounds.

Direct production of heterocyclic aromatic compounds from lignin ß-O-4 models remains a huge challenge due to the incompatible catalysis for aryl ether bonds cleavage and heterocyclic ring formation. Herein, the first example of quinoline synthesis from ß-O-4 model compounds by a one-pot cascade reaction is reported in yields up to 89 %. The reaction pathway involves selective cleavage of C-O bonds, dehydrogenation, aldol condensation, C-N bond formation along with heterocyclic aromatic ring construction. The control experiments suggest that both imine and chalcone were identified as the key intermediates, and the rate determining step as well as the preferred pathway were experimentally clarified and supported by density functional theory (DFT) calculations. Based on this protocol, the conversion of ß-O-4 polymer delivered 56 wt % yield of quinoline derivative in three steps. This transformation provides a potential petroleum-independent choice for heterocyclic aromatic chemicals.

Transition-metal-free synthesis of pyrimidines from lignin ß-O-4 segments via a one-pot multi-component reaction.

Heteroatom-participated lignin depolymerization for heterocyclic aromatic compounds production is of great importance to expanding the product portfolio and meeting value-added biorefinery demand, but it is also particularly challenging. In this work, the synthesis of pyrimidines from lignin ß-O-4 model compounds, the most abundant segment in lignin, mediated by NaOH through a one-pot multi-component cascade reaction is reported. Mechanism study suggests that the transformation starts by NaOH-induced deprotonation of Cα-H bond in ß-O-4 model compounds, and involves highly coupled sequential cleavage of C-O bonds, alcohol dehydrogenation, aldol condensation, and dehydrogenative aromatization. This strategy features transition-metal free catalysis, a sustainable universal approach, no need of external oxidant/reductant, and an efficient one-pot process, thus providing an unprecedented opportunity for N-containing aromatic heterocyclic compounds synthesis from biorenewable feedstock. With this protocol, an important marine alkaloid meridianin derivative can be synthesized, emphasizing the application feasibility in pharmaceutical synthesis.

Gold(I) Bis(1,2,3-triazol-5-ylidene) Complexes as Promising Selective Anticancer Compounds.

The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC50 values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 µM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.

Sustainable Production of Benzylamines from Lignin.

Catalytic conversion of lignin into heteroatom functionalized chemicals is of great importance to bring the biorefinery concept into reality. Herein, a new strategy was designed for direct transformation of lignin ß-O-4 model compounds into benzylamines and phenols in moderate to excellent yields in the presence of organic amines. The transformation involves dehydrogenation of Cα -OH, hydrogenolysis of the Cß -O bond and reductive amination in the presence of Pd/C catalyst. Experimental data suggest that the dehydrogenation reaction proceeds over the other two reactions and secondary amines serve as both reducing agents and amine sources in the transformation. Moreover, the concept of "lignin to benzylamines" was demonstrated by a two-step process. This work represents a first example of synthesis of benzylamines from lignin, thus providing a new opportunity for the sustainable synthesis of benzylamines from renewable biomass, and expanding the products pool of biomass conversion to meet future biorefinery demands.

Mimicking reactive high-valent diiron-µ2-oxo intermediates of nonheme enzymes by an iron tetracarbene complex.

The first diiron(iii,iv)-µ2-oxo tetracarbene complex is isolated and characterized by SC-XRD, UV/Vis, EPR, Evans' NMR and elemental analysis. CV indicates the presence of a transient high-valent diiron(iv)-µ2-oxo species. Its formation and decay is investigated via UV/Vis kinetics and NMR.

The organometallic ferrocene exhibits amplified anti-tumor activity by targeted delivery via highly selective ligands to αvß3, αvß6, or α5ß1 integrins.

High levels of reactive oxygen species (ROS) in tumors have been shown to exert anti-tumor activity, leading to the concept of ROS induction as therapeutic strategy. The organometallic compound ferrocene (Fc) generates ROS through a reversible one-electron oxidation. Incorporation of Fc into a tumor-targeting, bioactive molecule can enhance its therapeutic activity and enable tumor specific delivery. Therefore, we conjugated Fc to five synthetic, Arg-Gly-Asp (RGD)-based integrin binding ligands to enable targeting of the cell adhesion and signaling receptor integrin subtypes αvß3, α5ß1, or αvß6, which are overexpressed in various, distinct tumors. We designed and synthesized a library of integrin-ligand-ferrocene (ILF) derivatives and showed that ILF conjugates maintained the high integrin affinity and selectivity of their parent ligands. A thorough biological characterization allowed us to identify the two most promising ligands, an αvß3 (L2b) and an αvß6 (L3b) targeting ILF, which displayed selective integrin-dependent cell uptake and pronounced ferrocene-mediated anti-tumor effects in vitro, along with increased ROS production and DNA damage. Hence, ILFs are promising candidates for the selective, tumor-targeted delivery of ferrocene to maximize its anti-cancer efficacy and minimize systemic toxicity, thereby improving the therapeutic window of ferrocene compared to currently used non-selective anti-cancer drugs.

Visible Light-Induced Pericyclic Cascade Reaction for the Synthesis of Quinolinone Derivatives with an Oxabicyclo[4.2.0]octene Skeleton.

A photoinduced pericyclic cascade reaction has been developed to afford oxabicyclo[4.2.0]octenes. Mechanistic studies show that this reaction undergoes [2 + 2]-photocycloaddition, base-promoted elimination, retro-4π-electrocyclization, [1,5]-H shift, and 4π-electrocyclization procedures. This reaction features wide substrate scope, good functional group tolerance, and excellent diastereoselectivity.

Fluorescent palladium(II) and platinum(II) NHC/1,2,3-triazole complexes: antiproliferative activity and selectivity against cancer cells.

Fluorescent Pd(ii) and Pt(ii) complexes bearing 4-methylene-7-methoxycoumarin (MMC) and 2,6-diispropylphenyl (Dipp) substituted NHC/1,2,3-triazole hybrid ligands are described. Depending on the reaction conditions two different ligand coordination modes are observed, i.e., bidentate solely coordinating via NHCs or tetradentate coordinating via NHCs and 1,2,3-triazoles. All Dipp substituted complexes show antiproliferative activity against cervix (HeLa) and breast (MCF-7) human carcinoma cells. The activity significantly depends on the coordination mode, with the tetradentate motif being notably more effective (HeLa: IC50 = 3.9 µM to 4.7 µM; MCF-7: IC50 = 2.07 µM to 2.35 µM). Amongst the MMC series, only the Pd(ii) complex featuring the bidentate coordination mode is active against HeLa (IC50 = 6.1 µM). In contrast to its structurally related Dipp derivative (SI = 0.6), it shows a high selectivity for HeLa (SI > 16) compared to healthy skin cells (HaCaT). According to fluorescence microscopy, this compound is presumably located in late endosomes or lysosomes.

Activation of Molecular Oxygen by a Cobalt(II) Tetra-NHC Complex*.

The first dicobalt(III) µ2 -peroxo N-heterocyclic carbene (NHC) complex is reported. It can be quantitatively generated from a cobalt(II) compound bearing a 16-membered macrocyclic tetra-NHC ligand via facile activation of dioxygen from air at ambient conditions. The reaction proceeds via an end-on superoxo intermediate as demonstrated by EPR studies and DFT. The peroxo moiety can be cleaved upon addition of acetic acid, yielding the corresponding CoIII acetate complex going along with H2 O2 formation. In contrast, both CoII and CoIII complexes are also studied as catalysts to utilize air for olefin and alkane oxidation reactions; however, not resulting in product formation. The observations are rationalized by DFT-calculations, suggesting a nucleophilic nature of the dicobalt(III) µ2 -peroxo complex. All isolated compounds are characterized by NMR, ESI-MS, elemental analysis, EPR and SC-XRD.