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.

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.

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.

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.

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.

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.

Radiosynthesis and Preclinical Evaluation of Bispecific PSMA/FAP Heterodimers for Tumor Imaging.

Due to tumor heterogeneity and complex tumor-stromal interactions in multicellular systems, the efficiency of monospecific tracers for tumor diagnosis and therapy is currently limited. In light of the evidence of prostate-specific membrane antigen (PSMA) overexpression in tumor cells and fibroblast activation protein (FAP) upregulation in the tumor stroma, heterodimer dual targeting PSMA and FAP may have the potential to improve tumor diagnosis. Herein, we described the radiosynthesis, in vitro characterization, and micro-PET/CT imaging of two novel 18F-labeled bispecific PSMA/FAP heterodimers. 18F-labeled heterodimers showed high specificity and affinity targeting to PSMA and FAP in vitro and in vivo. Compared with the monospecific tracers [18F]AlF-PSMA-BCH and [18F]FAPI-42, both 18F-labeled heterodimers exhibited better tumor uptake in tumor-bearing mice. Their favorable characterizations such as convenient synthesis, high tumor uptake, and favorable pharmacokinetic profile could lead to their future applications as bispecific radiotracers for clinical cancer imaging.

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.

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.

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.

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.

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.

The investigation and bioorthogonal anticancer activity enhancement of a triphenylphosphine-labile prodrug of seleno-combretastatin-4.

Here, a triphenylphosphine (TPP)-labile prodrug of seleno-combretastatin-4 (CSeD) was designed and synthesized. A detailed investigation revealed that CSeD, which was shown to be very safe in circulating blood, could react with TPP to release CA-4 and a selenodiazole derivative, with accompanying powerful anticancer and antiangiogenesis effects, as well as radiosensitization properties.

Adjusting the lipid-water distribution coefficient of iridium(III) complexes to enhance the cellular penetration and treatment efficacy to antagonize cisplatin resistance in cervical cancer.

The effective design of metal complexes to manipulate their lipid-water distribution coefficient is an appealing strategy for improving their cellular penetration and treatment efficacy. Here, we conveniently synthesized three iridium (Ir) complexes with red fluorescence via the simple non-conjugate modification of the side arm of the ligand. Bio-evaluation revealed that upon adding non-conjugate selenium (Se) arene derivatives, the lipid-water distribution coefficient of Ir-Se was found to be suitable, not only decreasing the toxic side effects of complexes to normal cells, but also effectively improving their anticancer activity via enhancing their penetration into tumor cells. Moreover, mechanistic investigations demonstrated that Ir-Se entered R-HeLa cells through endocytosis, and triggered apoptosis via the down-regulation of the mitochondrial membrane potential and excessive production of singlet oxygen, thereby possessing a highly effective cytotoxicity to antagonize cisplatin resistance. Therefore, we developed a convenient strategy to derive functional metal complexes and revealed that the introduction of Se on the side arm of the ligand provided the complexes with the capacity to reverse multidrug resistance.

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.

Simple Aggregation-Induced Emission-Based Multifunctional Fluorescent Dots for Cancer Therapy In Vitro.

Multifunctional nanoparticles were simply synthesized by mixing a TICT+AIE featured molecule (TPAPP-CHO) with PBS solution. The fluorescent (FL) dots entered the cells via energy-related endocytosis and were located in lysosome emitting green FL. This indicated that the nanoparticles were dissociated in the lysosome. Moreover, the synthesized nanoparticles (NPs) demonstrate potent cytotoxicity against human U87 glioblastoma cells by inducing cell apoptosis via triggering intracellular ROS overproduction.

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.

Synthesis and Biological Evaluation of Reniochalistatins A-E and a Reniochalistatin E Analogue.

The total synthesis of reniochalistatins A-E, along with a reniochalistatin E analogue (inverso-E) was successfully achieved through Fmoc-based solid-phase peptide synthesis and subsequent macrolactamization with PyBOP and DIEA. The biological activities of these reniochalistatins and a key linear peptide intermediate were systematically evaluated. Among these seven synthesized compounds, linear reniochalistatin B was found to have potent activity against several cancer cell lines not shown by the cyclic reniochalistatin B counterpart. In addition, linear reniochalistatin B was found to have antitubercular activity (IC50 =1.4 µm). Inverso-E possesses increasing cytotoxicity against the HeLa and LNCaP cell lines after simple alternation of the sequence of amino acids in reniochalistatin E. The results of these studies provide a feasible method to further investigate the structure-activity relationships (SARs) of reniochalistatins A-E.