Electrochemically Direct Fluorination Functionalization of Styrenes with Different Fluorine Source: Access to Fluoroalkyl Derivatives.

A mild protocol for electrochemically oxidative fluorodifunctionalization of styrenes has been demonstrated. The reaction proceeds under metal, external oxidant, and catalyst free conditions, allowing tunable access to a wide variety of synthetically useful fluoroalkyl derivatives, such as ß-fluorosulfone/fluoromethyl, fluorothiocyanation, and vinylsulfonyl derivatives. Moreover, CsF was shown to be the proper fluorine source for this electrochemical fluorodifunctionalization transformation.

Sulfonated Polyimide Membranes Constructed by Main-Chain and Molecular-Network Engineering Strategy for Direct Methanol Fuel Cell.

Excessive swelling is one important factor that leads to high fuel permeability and limited operating concentration of methanol for proton exchange membranes. Herein, a collaborative strategy of main-chain and molecular-network engineering is applied to lower swelling ratio and improve methanol resistance for highly sulfonated polyimide. Two m-phenylenediamine monomers (4-(2,3,5,6-tetrafluoro-4-vinylphenoxy)benzene-1,3-diamine and 4,6-bis(2,3,5,6-tetrafluoro-4-vinylphenoxy)benzene-1,3-diamine) with tetrafluorostyrol groups are designed and synthesized. Two series of cross-linked sulfonated polyimides (CSPI-Ts, CSPI-Bs) are prepared from the two diamines, 4,4'-diaminostilbene-2,2'-disulfonic acid and 1,4,5,8-naphthalenetetracarboxylicdianhydride. The rigid main-chain structure is cornerstone for wet CSPI-Ts and CSPI-Bs remaining stable at elevated temperatures. The introduction of hydrophobic cross-linked network further improves their dimensional stability and methanol resistance. CSPI-Ts and CSPI-Bs show obviously improved performances containing high proton conductivity (121 ± 0.27-158 ± 0.35 S cm-1 ), low swelling ratio (9.6 ± 0.40%-16.1 ± 0.01%) and methanol permeability (4.14-7.69 × 10-7 cm2 s-1 ) at 80 °C. The direct methanol fuel cell (DMFC) is assembled from CSPI-T-10 with balanced properties, and it exhibits high maximum power density (PDmax ) of 82.3 and 72.6 mW cm-2 in 2 and 10 m methanol solution, respectively. The ratio of PDmax in 10 m methanol solution to the value in 2 m methanol solution is as high as 88%. The CSPI-T-10 is promising proton exchange membrane candidate for DMFC application.

Piezo-catalysis Mechanism Elucidation by Tracking Oxygen Reduction to Hydrogen Peroxide with In situ EPR Spectroscopy.

For piezoelectric catalysis, the catalytic mechanism is a topic of great controversy, with debates centered around whether it belongs to the energy band theory or the screening charge effect which are similar to mechanisms of photocatalysis and electrochemical catalysis, respectively. Due to the formation of different intermediate active-species during two-electron oxygen reduction reaction (ORR) via electro- and photo-catalysis, the key to solving this problem is precisely monitoring the active species involved in ORR during electro-, photo-, and piezo-catalysis under identical condition. Here, a semiconductor material, BiOBr with abundant oxygen vacancies (BOB-OV) was found remarkable catalytic activity in H2O2 production by all three catalytic methods. By employing in situ electron paramagnetic resonance (EPR) spectroscopy, the H2O2 evolution pathway through piezo-catalysis over BOB-OV was monitored, which showed a similar reaction pathway to that observed in photo-catalytic process. This finding represents solid evidence supporting the notion that piezo-catalytic mechanism of ORR is more inclined towards photo-catalysis rather than electro-catalysis. Significantly, this exploratory conclusion provides insight to deepen our understanding of piezo-catalysis.

Elastic-Electric Coefficient-Sensitive Hydrogel Sensors toward Sweat Detection.

The complex and multivariate biological systems and environment are challenging the development of related detection and analysis. It calls for the multiresponsive and facile sensing material and method for multi-analyte identification. In this work, we proposed an elastic-electric coefficient sensitivity strategy with hydrogel [amino trimethylene phosphonic acid-assisted poly(vinyl alcohol)] to achieve discriminative analysis of various chemicals. Elastic sensitivity based on the Hofmeister effect and electric sensitivity based on hydrated ion migration are explored in detail. With a rational design, the elastic-electric coefficient-sensitive hydrogel can qualify and quantify various kinds of chemicals (cations, anions, amino acids, saccharides, and lactate). The facile hydrogel sensor realized complicated sweat recognition and can be used in various applications such as environment monitoring, disease diagnosis, and athletic training optimization.

18F- or 177Lu-labeled bivalent ligand of fibroblast activation protein with high tumor uptake and retention.

PURPOSE: Fibroblast activation protein (FAP) has become a promising cancer-related target for diagnosis and therapy. The aim of this study was to develop a bivalent FAP ligand for both diagnostic PET imaging and endoradiotherapy. METHODS: We synthesized a bivalent FAP ligand (ND-bisFAP) and labeled it with 18F or 177Lu. FAP-positive A549-FAP cells were used to study competitive binding to FAP, cellular internalization, and efflux properties in vitro. Micro-PET imaging with [18F]AlF-ND-bisFAPI was conducted in mice bearing A549-FAP or U87MG tumors. Biodistribution and therapeutic efficacy of [177Lu]Lu-ND-bisFAPI were conducted in mice bearing A549-FAP tumors. RESULTS: The FAP binding affinity of ND-bisFAPI is 0.25 ± 0.05 nM, eightfold higher in potency than the monomeric DOTA-FAPI-04 (IC50 = 2.0 ± 0.18 nM). In A549-FAP cells, ND-bisFAPI showed specific uptake, a high internalized fraction, and slow cellular efflux. Compared to the monomeric [18F]AlF-FAPI-42, micro-PET imaging with [18F]AlF-ND-bisFAPI showed higher specific tumor uptake and retention for at least 6 h. Biodistribution studies showed that [177Lu]Lu-ND-bisFAPI had higher tumor uptake than [177Lu]Lu-FAPI-04 at the 24, 72, 120, and 168 h time points (all P < 0.01). [177Lu]Lu-ND-bisFAPI delivered fourfold higher radiation than [177Lu]Lu-FAPI-04 to A549-FAP tumors. For the endoradiotherapy study, 37 MBq of [177Lu]Lu-ND-bisFAPI significantly reduced tumor growth compared to the same dose of [177Lu]Lu-FAPI-04. Half of the dose of [177Lu]Lu-ND-bisFAPI (18.5 MBq) has comparable median survival as 37 MBq of [177Lu]Lu-FAPI-04 (37 vs 36 days). CONCLUSION: The novel bivalent FAP ligand was developed as a theranostic radiopharmaceutical and showed promising properties including higher tumor uptake and retention compared to the established radioligands [18F]AlF-FAPI-42 and [177Lu]Lu-FAPI-04. Preliminary experiments with 18F- or 177Lu-labeled ND-bisFAPI showed promising imaging properties and favorable anti-tumor responses.

A Diverse Micromorphology of Photonic Crystal Chips for Multianalyte Sensing.

The diversity by nano/microstructural material or device constructing can provide the exciting opportunity for sensitivity and selectivity to achieve facile and efficient multianalyte recognition for clinical diagnosis, environment monitoring, etc., in complex system analysis. Colloidal poly(styrene-methyl methacrylate-acrylic acid) (poly(St-MMA-AA)) nanoparticle-assembled photonic crystals (PCs) can achieve manipulative 3D structural colors and approach PC sensor chip for high-efficient multianalysis utilizing simple dye. Focusing on the morphology effects of structural color, a PC microchip is designed and constructed with various geometrical micromorphologies. Based on the angle dependence of colloidal-crystal structural color, the stopband distribution is explored on various morphological PC pixels. Selective fluorescent enhancement is realized for stopband-matched PCs, which approach the successful discrimination of metal ions and complex multianalysis of groundwater. Meanwhile, printed droplet-shaping manipulation can achieve a large-scale structural-color sensor array of chips with designable nano/microstructures via colloidal assembly. It will be the critical puzzle piece between macromorphology and microstructure for the structural-color researches.

Novel 18F-Labeled Isonicotinamide-Based Radioligands for Positron Emission Tomography Imaging of Glycogen Synthase Kinase-3ß.

Glycogen synthase kinase-3ß (GSK-3ß), a cytoplasmic serine/threonine protein kinase, is involved in several human pathologies including Alzheimer's disease, bipolar disorder, diabetes, and cancer. Positron emission tomography (PET) imaging of GSK-3ß could aid in investigating GSK-3ß levels under normal and pathological conditions. In this study, we designed and synthesized fluorinated PET radioligands starting with recently identified isonicotinamide derivatives that showed potent affinity to GSK-3ß. After extensive in vitro inhibitory activity assays and analyzing U87 cell uptake, we identified [18F]10a-d as potential tracers with good specificity and high affinity. They were then subjected to further in vivo evaluation in rodent brain comprising PET imaging and metabolism studies. The radioligands [18F]10b-d penetrated the blood-brain barrier and accumulated in GSK-3ß-rich regions, including amygdala, cerebellum, and hippocampus. Also, it could be specifically blocked using the corresponding standard compounds. With these results, this work sets the basis for further development of novel 18F-labeled GSK-3ß PET probes.

Electro-Oxidative C-N Bond Formation through Azolation of Indole Derivatives: An Access to 3-Substituent-2-(Azol-1-yl)indoles.

A practical protocol to synthesize 3-substituent-2-(azol-1-yl)indole derivatives has been developed via an electrochemical oxidative cross coupling process under mild conditions. This electro-oxidative C-N bond formation strategy tolerates a range of functional groups and is amenable to gram scale synthesis. Moreover, this method was applied to the late-stage functionalization of bioactive molecules.

Renewable Castor-Oil-based Waterborne Polyurethane Networks: Simultaneously Showing High Strength, Self-Healing, Processability and Tunable Multishape Memory.

Materials with multifunctionality or multiresponsiveness, especially polymers derived from green, renewable precursors, have recently attracted significant attention resulting from their technological impact. Nowadays, vegetable-oil-based waterborne polyurethanes (WPUs) are widely used in various fields, while strategies for simultaneous realization of their self-healing, reprocessing, shape memory as well as high mechanical properties are still highly anticipated. We report development of a multifunctional castor-oil-based waterborne polyurethane with high strength using controlled amounts of dithiodiphenylamine. The polymer networks possessed high tensile strength up to 38 MPa as well as excellent self-healing efficiency. Moreover, the WPU film exhibited a maximum recovery of 100 % of the original mechanical properties after reprocessing four times. The broad glass-transition temperature of the samples endowed the films with a versatile shape-memory effect, including a dual-to-quadruple shape-memory effect.

Photodriven Regeneration of G-Quadruplex Aptasensor for Sensitively Detecting Thrombin.

Aptamers have been widely used as recognition elements in electrochemical sensors. However, as the most expensive consumable, the aptasensors regeneration is still a critical challenge for sustainable feasibility and attracting great interest from researchers, due to the high affinity between the aptamers and their targets (the dissociation constant Kd is low to subnanomolar or nanomolar). In this work, we propose a photochromic five-azobenzene-inserted thrombin-aptamer based aptasensor to improve the regenerativity. With ultraviolet light exposure, the trans-structure of azobenzene changes to cis-structure, and open the folded aptamer to realize the aptasensor regeneration. The limit of detection can be sensitive to 3 pM (S/N = 3). The thrombin concentrations were detected to be 2.48 ± 0.02 and 20.26 ± 0.98 nM (n = 3) in duck whole blood and blood serum, respectively. Utilizing surface plasmon resonance, we demonstrated that the certain azobenzene moieties can exactly increase Kd of aptamer-thrombin bounding. The photodriven conversion of thrombin-aptamer from G-quadruplex to loosen structure approaches a convenient regeneration for aptasensor, which will promote its popularization and sustainable feasibility.

Electrooxidative and Regioselective C-H Azolation of Phenol and Aniline Derivatives.

A general and practical protocol was developed for the regioselective C-H azolation of phenol and aniline derivatives by electrooxidative cross-coupling. The reaction occurs under metal-, oxidant-, and reagent-free conditions, allowing access to a wide variety of synthetically useful heteroarene derivatives. The reaction also tolerates a broad range of functional groups and is amenable to gram-scale synthesis. Finally, a preliminary mechanistic study indicated that a radical-radical-combination pathway might be involved in the coupling reaction.

Trifluoromethoxylation of arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration.

Aryl trifluoromethoxylation by a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxylamine derivatives and intramolecular OCF3  migration is presented. This protocol allows easy access to a wide range of synthetically useful ortho-OCF3 aniline derivatives. In addition, it utilizes bench-stable reagents, is operationally simple, shows high functional-group tolerance, and is amenable to gram-scale as well as one-pot synthesis. A reaction mechanism of a heterolytic cleavage of the NOCF3 bond followed by recombination of the resulting nitrenium ion and trifluoromethoxide is proposed for the OCF3 -migration reaction.

Electrochemical Fluorination Functionalization of gem-Difluoroalkenes with CsF as a Fluorine Source: Access to Fluoroalkyl Building Blocks.

Using easily handled CsF as a fluorine source, an electrochemically metal-free protocol for chemo- and regioselective synthesis of various types of long-chain perfluoroalkyl aromatics with gem-difluoroalkene as a substrate and an alcohol or azole as an additional nucleophile was developed. The eletrochemical transformation could tolerate several functional groups, such as halogens, cyanos, benzyls, and heterocycles, and is amenable to gram-scale. The application of this electrochemical method in radiofluorination was also tested.

Human/mouse CD137 agonist, JNU-0921, effectively shrinks tumors through enhancing the cytotoxicity of CD8+ T cells in cis and in trans.

Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8+ T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.

A concise approach to the spiroiminal fragment of marineosins.

A concise approach to the spiroiminal fragment of marineosins A and B is described. The key steps involve an acid-catalyzed N-acyliminium ion cyclization and a Vilsmeier-Haack type reaction with Tf2O.

Isolation and total synthesis of dysidone A: a new piperidone alkaloid from the marine sponge Dysidea sp.

A new piperidone alkaloid, dysidone A (1), was isolated from the marine sponge Dysidea sp. The structure of 1 was elucidated by the method of spectroscopic analysis. Compound 1 represented the first example of piperidone alkaloid isolated from the sponge of the genus Dysidea with the exocyclic double bond. Furthermore, the total synthesis of 1 was also carried out, which was started with piperidine proceeding a PIDA/I2-mediated α and ß-C (sp3) -H bond dual oxygenation to achieve a 5-steps synthesis in a total yield of 10.6%. In addition, the anti-inflammatory activities of 1 and its derivative dysidone B (1d) were evaluated, which suggested that 1 showed weak anti-inflammatory activity.

Synthesis and preclinical evaluation of a heterodimeric radioligand targeting fibroblast activation protein and integrin-αvß3.

Tumor progression is accompanied by intrinsic heterogeneity and different phenotypes, which implies a different expression of cell surface receptors. Fibroblast activation protein (FAP) and integrin αvß3 are highly expressed in the cell surface of cancer-associated cells or cancer cells compared with normal cells. Therefore, a FAP/integrin αvß3 bispecific heterodimer was developed for positron emission tomography (PET) diagnostic imaging and radiotherapy. The heterodimer DOTA-FAPI-RGD was labeled with the diagnostic radionuclide gallium-68 or the therapeutic radionuclide lutetium-177, with yields >80%, and high stability. The competitive displacement binding assay showed an IC50 = 6.8 ± 0.6 nM for DOTA-FAPI-RGD towards FAP and IC50 = 2.1 ± 0.4 nM towards integrin αvß3. Radionuclide labeled DOTA-FAPI-RGD showed high specificity and rapid internalization into U87MG cells (FAP/αvß3-positive) in vitro. Micro-PET and biodistribution studies of [68Ga]Ga-DOTA-FAPI-RGD in tumor-bearing mice demonstrated that a high and specific tumor uptake of the tracer and a fast body clearance, resulting in high contrast images. In addition to the imaging applications demonstrated in this study, the labeling of the heterodimeric ligand with the radionuclide lutetium-177 used in cancer treatment might allow the therapeutic application of this ligand.

Electrochemical Difunctionalization of gem-Difluoroalkenes: A Metal-Free Synthesis of α-Difluoro(alkoxyl/azolated) Methylated Ethers.

A scalable electrochemical difunctionalization of gem-difluoroalkenes to structurally versatile difluoro motifs was achieved. This methodology features reagent-free conditions, good functional group tolerance, and a relatively broad substrate scope. Meanwhile, the electrolysis protocol is easy to handle, and the products show good regio- and chemoselectivity. The reaction mechanism was also preliminarily studied.

Stereoselective construction of the tetracyclic core of Cryptotrione.

An efficient stereoselective approach to the tetracyclic core of Cryptotrione, involving an asymmetric Michael addition, ring-closing metathesis, and subsequent cyclopropanation, is described.

In vivo genome-wide CRISPR screening identifies ZNF24 as a negative NF-κB modulator in lung cancer.

Systemic identification of tumor suppressor genes (TSGs) and elucidation of their signaling provide a new angle for understanding of tumorigenesis, which is important for developing successful treatment for lung cancer patients. In our current work, we conducted an in vivo screen for lung cancer TSGs through CRISPR/Cas9 mediated knockout of genes at genome-wide scale. We found that ZNF24 was a potent and clinically relevant TSG of lung cancer. Ectopic expression of ZNF24 arrested lung cancer cells in S phase. Mechanistically, ZNF24 bound to promoter region of P65 to negatively regulate its transcription and thereby the signaling activity of NF-κB pathway. This signaling cascade is clinically relevant. Importantly, we found that combinational inhibition of KRAS, NF-κB, and PD-1 effectively shrank autochthonous KrasG12D/ZNF24-/- lung cancers in transgenic mouse model. Our current work thus revealed an important role played by loss of function of ZNF24 in lung tumorigenesis and shed new light in precision medicine for a portion of lung cancer patients.