Facial synthesis of fluorine-engineered magnetic covalent organic framework for selective and ultrasensitive determination of fipronil, its metabolites and analogs in food samples.

To improve the adsorption affinity and selectivity of fipronils (FPNs), including fipronil, its metabolites and analogs, a magnetic covalent organic framework (Fe3O4@COF-F) with copious fluorine affinity sites was innovatively designed as an adsorbent of magnetic solid-phase extraction (MSPE). The enhanced surface area, pore size, crystallinity of Fe3O4@COF-F and its exponential adsorption capacities (187.3-231.5 mg g-1) towards fipronils were investigated. Combining MSPE with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), an analytical method was established for the selective determination of fipronils in milk and milk powder samples. This method achieved high sensitivity (LODs: 0.004-0.075 ng g-1), satisfactory repeatability and accuracy with spiked recoveries ranging from 89.9% to 100.3% (RSDs≤5.1%). Overall, the constructed Fe3O4@COF-F displayed great potential for the selective enrichment of fipronils, which could be ascribed to fluorine­fluorine interaction. This method proposed a feasible and promising strategy for the development of functionalized COF and broadened its application in fluorine containing hazards detection.

Novel Copper (II) Complexes with Fluorine-Containing Reduced Schiff Base Ligands Showing Marked Cytotoxicity in the HepG2 Cancer Cell Line.

Several novel copper (II) complexes of reduced Schiff bases containing fluoride substituents were prepared and structurally characterized by single-crystal X-ray diffraction. The complexes exhibited diverse structures, with the central atom in distorted tetrahedral geometry. The biological effects of the products were evaluated, specifically their cytotoxicity, antimicrobial, and antiurease activities, as well as affinity for albumin (BSA) and DNA (ct-DNA). The complexes showed marked cytotoxic activities in the HepG2 hepatocellular carcinoma cell line, considerably higher than the standard cisplatin. The cytotoxicity depended significantly on the substitution pattern. The best activity was observed in the complex with a trifluoromethyl group in position 4 of the benzene ring-the dichloro[(±)-trans-N,N'-bis-(4-trifluoromethylbenzyl)-cyclohexane-1,2-diamine]copper (II) complex, whose activity (IC50 28.7 µM) was higher than that of the free ligand and markedly better than the activity of the standard cisplatin (IC50 336.8 µM). The same complex also showed the highest antimicrobial effect in vitro. The affinity of the complexes towards bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) was established as well, indicating only marginal differences between the complexes. In addition, all complexes were shown to be excellent inhibitors of the enzyme urease, with the IC50 values in the lower micromolar region.

Hyperbranched Polymeric 19F MRI Contrast Agents with Long T2 Relaxation Time Based on ß-Cyclodextrin and Phosphorycholine.

19F magnetic resonance imaging (19F MRI) is gaining attention as an emerging diagnostic technology. Effective 19F MRI contrast agents (CAs) for in vivo applications require a long transverse (or spin-spin) relaxation time (T2), short longitudinal (or spin-lattice) relaxation time (T1), high fluorine content, and excellent biocompatibility. Here, we present a novel hyperbranched polymeric 19F MRI CA based on ß-cyclodextrin and phosphorylcholine. The influence of the branching degree and fluorine content on T2 was thoroughly investigated. Results demonstrated a maximum fluorine content of 11.85% and a T2 of 612 ms. This hyperbranched polymeric 19F MRI CA exhibited both great biocompatibility against cells and organs of mice and high-performance imaging capabilities both in vitro and in vivo. The research provides positive insights into the synthesis strategies, topological design, and selection of fluorine tags for 19F MRI CAs.

Recent Advances on Fluorine Chemistry.

The purpose of this Special Issue is to showcase the latest findings in fluorine chemistry [...].

19F NMR Reveals the Dynamics of Substrate Binding and Lid Closure for Iodotyrosine Deiodinase as a Complement to Steady-State Kinetics and Crystallography.

Active site lids are common features of enzymes and typically undergo conformational changes upon substrate binding to promote catalysis. Iodotyrosine deiodinase is no exception and contains a lid segment in all of its homologues from human to bacteria. The solution-state dynamics of the lid have now been characterized using 19F NMR spectroscopy with a CF3-labeled enzyme and CF3O-labeled ligands. From two-dimensional 19F-19F NMR exchange spectroscopy, interconversion rates between the free and bound states of a CF3O-substituted tyrosine (45 ± 10 s-1) and the protein label (40 ± 3 s-1) are very similar and suggest a correlation between ligand binding and conformational reorganization of the lid. Both occur at rates that are ∼100-fold faster than turnover, and therefore these steps do not limit catalysis. A simple CF3O-labeled phenol also binds to the active site and induces a conformational change in the lid segment that was not previously detectable by crystallography. Exchange rates of the ligand (130 ± 20 s-1) and protein (98 ± 8 s-1) in this example are faster than those above but remain self-consistent to affirm a correlation between ordering of the lid and binding of the ligand. Both ligands also protect the protein from limited proteolysis, as expected from their ability to stabilize a compact lid structure. However, the minimal turnover of simple phenol substrates indicates that such stabilization may be necessary but is not sufficient for efficient catalysis.

Stimuli-Responsive Polymers for Advanced 19F Magnetic Resonance Imaging: From Chemical Design to Biomedical Applications.

Fluorine magnetic resonance imaging (19F MRI) is a rapidly evolving research area with a high potential to advance the field of clinical diagnostics. In this review, we provide an overview of the recent progress in the field of fluorinated stimuli-responsive polymers applied as 19F MRI tracers. These polymers respond to internal or external stimuli (e.g., temperature, pH, oxidative stress, and specific molecules) by altering their physicochemical properties, such as self-assembly, drug release, and polymer degradation. Incorporating noninvasive 19F labels enables us to track the biodistribution of such polymers. Furthermore, by triggering polymer transformation, we can induce changes in 19F MRI signals, including attenuation, amplification, and chemical shift changes, to monitor alterations in the environment of the tracer. Ultimately, this review highlights the emerging potential of stimuli-responsive fluoropolymer 19F MRI tracers in the current context of polymer diagnostics research.

Incorporation of CF3-pseudoprolines into polyproline type II foldamers confers promising biophysical features.

The development and the use of fluorinated polyproline-type II (PPII) foldamers are still underexplored. Herein, trifluoromethyl pseudoprolines have been incorporated into polyproline backbones without affecting their PPII helicity. The ability of the trifluoromethyl groups to increase hydrophobicity and to act as 19F NMR probes is demonstrated. Moreover, the enzymatic stability and the non-cytotoxicity of these fluorinated foldamers make them valuable templates for use in medicinal chemistry.

Donor-acceptor type COFs with multiple fluorine groups as electron storage units to promote antimicrobial performance.

The novel donor-acceptor (D-A) type covalent organic frameworks TATF-COF and TATP-COF, with multiple fluorine groups as electron storage units, were successfully constructed to achieve efficient charge transfer and photocatalytic activity for antibacterial photocatalytic therapy. Fluorine, the most electronegative element, was utilized as an electron-withdrawing substituent for the acceptor, which could unite the donor unit together and efficiently improve the charge transfer from the donor to acceptor. The unique D-A structures of TATF-COF and TATP-COF ensure that they have narrow band gaps, strong photocurrent responses, long fluorescence lifetimes, and good capacity to generate reactive oxygen species (ROS) to realize good antibacterial activity. Meanwhile, the inclusion of multiple hydrophilic fluorine groups means that TATF-COF and TATP-COF are highly water dispersible, which is also beneficial in terms of promoting the generation of adequate quantities of ROS. Hence, in view of their excellent photoelectric properties and good water dispersibility, further investigations were performed, and excellent antibacterial activities in vitro against both gram-negative and gram-positive bacteria were demonstrated for TATF-COF and TATP-COF. In addition, we also showed that they can function as effective antibacterial dental materials.

Maximizing the wetting resistance of fluorine-free omniphobic membranes for hypersaline wastewater desalination.

Membrane distillation (MD) equipped with omniphobic (non-wetting) membranes has found a niche in water reclamation from hypersaline industrial wastewater. Here, we examined the efficacy of non-fluorinated materials as surface coating agents for omniphobic MD membrane fabrication, and identified necessary mechanisms to attain a maximized wetting resistance using fluorine-free materials. We first prepared MD membranes with different surface chemistries using a series of linear alkylsilanes and polydimethylsiloxane (PDMS) as representative fluorine-free, low surface energy materials. Membranes modified with a longer chain alkylsilane exhibited a lower surface energy and demonstrated a greater wetting resistance in direct contact MD experiments using feedwaters of various surface tensions. Despite the nearly identical surface energy measured for the longest alkylsilane and PDMS, PDMS-modified membrane exhibited an extended antiwetting performance as compared to the membrane treated with the longest alkylsilane. To elucidate the source of the distinctive wetting resistance, we examined the nucleation and condensation kinetics on the surfaces with the different surface chemistries via environmental scanning electron microscopy. Our analysis suggests that the membranes treated with long chain alkylsilanes contain surface defects (i.e., hydrophilic regions) whereas the high mobility of the PDMS effectively minimizes the defect exposure, slowing down the condensation and subsequent surface wetting.

Innovative reuse of mineral waste for treatment of a contaminated soil by fluorine: synthesis of hydroxyapatite (HAP) and chemical performance assessments.

This research aimed to introduce a novel method for the valorization of mineral waste, focusing on the development of hydroxyapatite (HAP) as an effective and economical adsorbent for immobilizing fluoride ions (F-) in soil. Hydroxyapatites were produced through the reaction between potassium dihydrogen phosphate (KH2PO4) and calcium-abundant limestone soil (CLS). X-ray diffraction analyses revealed that the primary phases in HAPCLS were brushite (CaHPO5·2H2O) and hydroxyapatite (Ca10(PO4)6(OH)2). The FTIR spectra exhibited characteristics akin to natural HAP, including the presence of orthophosphate groups (PO43-), hydroxyl groups (OH-), and both A/B types of carbonates in the apatite structure. The morphology of the synthesized HAP, as observed through SEM-EDS, was consistent with that of phosphocalcic hydroxyapatite crystals. The EDS results indicated a Ca/P atomic ratio of 1.7 for HAPCLS, aligning closely with the typical hydroxyapatite stoichiometry (Ca/P = 1.67). The application of HAP to reduce fluoride (F-) levels in soil proved to be successful; introducing 1% of various HAP formulations reduced the fluoride concentration from 51.4 mg/kg in untreated soil to levels below the IWSI limit (10 mg/kg), achieving a reduction to 8.1 mg/kg for HAPCLS. The sequential extraction of fluoride demonstrated that after soil treatment, fluoride was predominantly removed from the residual fraction (Fraction 4) and was effectively sequestered by the hydroxyapatites (Ca10(PO4)6(OH)2) through anionic exchange with hydroxide ions (OH-), resulting in the formation of stable and insoluble fluorapatite (Ca10(PO4)6F2).

Identification of 6-Fluorine-Substituted Coumarin Analogues as POLRMT Inhibitors with High Potency and Safety for Treatment of Pancreatic Cancer.

Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7, which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.

The catalytic asymmetric polyene cyclization of homofarnesol to ambrox.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1-3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4-7. Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis8-10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

A polymeric 1H/19F dual-modal MRI contrast agent with a snowman-like Janus nanostructure.

Magnetic resonance imaging (MRI) has emerged as a pivotal tool in contemporary medical diagnostics, offering non-invasive and high-resolution visualization of internal structures. Contrast agents are essential for enhancing MRI resolution, accurate lesion detection, and early pathology identification. While gadolinium-based contrast agents are widely used in clinics, safety concerns have prompted exploration of metal-free alternatives, including fluorine and nitroxide radical-based MRI contrast agents. Fluorine-containing compounds exhibit excellent MRI capabilities, with 19F MRI providing enhanced resolution and quantitative assessment. Nitroxide radicals, such as PROXYL and TEMPO, offer paramagnetic properties for MRI contrast. Despite their versatility, nitroxide radicals suffer from lower relaxivity values (r1) compared to gadolinium. Dual-modal imaging, combining 1H and 19F MRI, has gained prominence for its comprehensive insights into biological processes and disease states. However, existing dual-modal agents predominantly utilize gadolinium-organic ligands without incorporating nitroxide radicals. Here, we introduce a novel dual-modal MRI contrast agent (J-CA) featuring a Janus asymmetric nanostructure synthesized via seeded emulsion polymerization and post-modification. J-CA demonstrates excellent in vitro and in vivo performance in both 19F and 1H MRI, with a T2 relaxation time of 5 ms and an r1 value of 0.31 mM-1 s-1, ensuring dual-modal imaging capability. Moreover, J-CA exhibits superior biocompatibility and organ targeting, making it a promising candidate for precise lesion imaging and disease diagnosis. This work introduces a new avenue for metal-free dual-modal MRI, addressing safety concerns associated with traditional contrast agents.

Efficient recovery of highly pure CaF2 from fluorine-containing wastewater using an icy lime solution.

Developing a feasible and low-cost strategy for the recovery of calcium fluoride efficiently from fluoride-containing wastewater is very essential for the recycle of fluoride resources. Herein, a modified lime precipitation method was employed to recover CaF2 from fluorinated wastewater using a special icy lime solution. Intriguingly, the highest F- removal was greater than 95% under the optimal condition, leaving a fluoride concentration from 200 to 8.64 mg/L, while the lime dosage was much lower than that of industry. Importantly, spherical-shaped CaF2 particles with a 93.47% purity and size smaller than 600 nm were recovered, which has a high potential for the production of hydrofluoric acid. Besides, the precipitation was significantly affected by Ca/F molar ratio, stirring time, temperature, and solution pH. Furthermore, the thermodynamics and kinetics were investigated in detail to reveal the crystallization process. As a result, the defluorination reaction followed the pseudo-second order reaction kinetics model. Also, CO2 in the air adversely influenced the CaF2 purity. Based on this facile method, a high lime utilization efficiency was applied to defluorination, which contributed to protecting the environment and saving costs. This study, therefore, provides a feasible approach for the green recovery of fluorine resources and has significance for related research.

Fluorine-functionalized covalent organic framework coated solid-phase microextraction probe coupled with electrospray ionization mass spectrometry for monitoring triclosan, triclocarban, and chlorophenols in mice.

Triclosan (TCS), triclocarban (TCC), and chlorophenols (CPs) are broad-spectrum antibacterials widely used in dermatological and oral hygiene products, which could induce severe liver and intestine injuries. Hence, it is essential to establish a rapid and sensitive method to monitor TCS, TCC, and CPs in various organisms. In this work, fluorine-functionalized covalent organic framework (COF-F) was prepared by using 4,4',4''-(1,3,5-triazine-2,4,6-triyl)tri-aniline and 2,3,5,6-tetrafluoroterephthalaldehyde as two building units and employed as a solid phase microextraction (SPME) probe for the extraction of TCS, TCC and CPs. The COF-F possessed excellent hydrophobicity, a large specific surface area (1354.3 m2 g-1) and high uniform porosity (3.2 nm), which facilitated high selectivity and adsorption properties towards TCS, TCC, and CPs. Therefore, the as-prepared COF-F-SPME in combination with electrospray ionization mass spectrometry has been developed to provide fast and ultrasensitive detection of TCS, TCC, and CPs in biological samples. The established method demonstrated satisfactory linear ranges (0.01-100.00 µg L-1) and low limits of detection (0.003-0.040 µg L-1) for TCS, TCC and CPs. The developed method could be successfully applied to detect TCS, TCC and CPs in the liver and kidney tissues of mice, demonstrating the potential for the detection of chlorinated aromatic pollutants in the biological samples.

Synthetic approaches and application of representative clinically approved fluorine-enriched anti-cancer medications.

Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.

19F Fast Magic-Angle Spinning NMR Spectroscopy on Microcrystalline Complexes of Fluorinated Ligands and the Carbohydrate Recognition Domain of Galectin-3.

Structural characterization of protein-ligand binding interfaces at atomic resolution is essential for improving the design of specific and potent inhibitors. Herein, we explored fast 19F- and 1H-detected magic angle spinning NMR spectroscopy to investigate the interaction between two fluorinated ligand diastereomers with the microcrystalline galectin-3 carbohydrate recognition domain. The detailed environment around the fluorine atoms was mapped by 2D 13C-19F and 1H-19F dipolar correlation experiments and permitted characterization of the binding interface. Our results demonstrate that 19F MAS NMR is a powerful tool for detailed characterization of protein-ligand interfaces and protein interactions at the atomic level.

Fluorinated 1,7-DO2A-Based Iron(II) Complexes as Sensitive 19F MRI Molecular Probes for Visualizing Renal Dysfunction in Living Mice.

Kidney diseases have become an important global health concern due to their high incidence, inefficient diagnosis, and poor prognosis. Devising direct methods, especially imaging means, to assess renal function is the key for better understanding the mechanisms of various kidney diseases and subsequent development of effective treatment. Herein, we developed a fluorinated ferrous chelate-based sensitive probe, 1,7-DO2A-Fe(II)-F18 (Probe 1), for 19F magnetic resonance imaging (MRI). This highly fluorinated probe (containing 18 chemically equivalent 19F atoms with a fluorine content at 35 wt %) achieves a 15-time enhancement in signal intensity compared with the fluorine-containing ligand alone due to the appropriately regulated 19F relaxation times by the ferrous ion, which significantly increases imaging sensitivity and reduces acquisition time. Owing to its high aqueous solubility, biostability, and biocompatibility, this probe could be rapidly cleared by kidneys, which provides a means for monitoring renal dysfunction via 19F MRI. With this probe, we accomplish in vivo imaging of the impaired renal dysfunction caused by various kidney diseases including acute kidney injury, unilateral ureteral obstruction, and renal fibrosis at different stages. Our study illustrates the promising potential of Probe 1 for in vivo real-time visualization of kidney dysfunction, which is beneficial for the study, diagnosis, and even stratification of different kidney diseases. Furthermore, the design strategy of our probe is inspiring for the development of more high-performance 19F MRI probes for monitoring various biological processes.

Quantifying CO-release from a photo-CORM using 19F NMR: An investigation into light-induced CO delivery.

Carbon monoxide (CO) is an innate signaling molecule that can regulate immune responses and interact with crucial elements of the circadian clock. Moreover, pharmacologically, CO has been substantiated for its therapeutic advantages in animal models of diverse pathological conditions. Given that an excessive level of CO can be toxic, it is imperative to quantify the necessary amount for therapeutic use accurately. However, estimating gaseous CO is notably challenging. Therefore, novel techniques are essential to quantify CO in therapeutic applications and overcome this obstacle precisely. The classical Myoglobin (Mb) assay technique has been extensively used to determine the amount of CO-release from CO-releasing molecules (CORMs) within therapeutic contexts. Nevertheless, specific challenges arise when applying the Mb assay to evaluate CORMs featuring innovative molecular architectures. Here, we report a fluorinated photo-CORM (CORM-FBS) for the photo-induced CO-release. We employed the 19F NMR spectroscopy approach to monitor the release of CO as well as quantitative evaluation of CO release. This new 19F NMR approach opens immense opportunities for researchers to develop reliable techniques for identifying molecular structures, quantitative studies of drug metabolism, and monitoring the reaction process.

A Fragment-Based Competitive 19F†LB-NMR Platform For Hotspot-Directed Ligand Profiling.

Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites. Herein, we describe a fragment-based competitive 19F Ligand Based NMR (LB-NMR) screening platform that enables routine, quantitative ligand profiling focused at ligand-binding hotspots. As a proof of concept, the method was applied to 4'-phosphopantetheine adenylyltransferase (PPAT) from Mycobacterium abscessus (Mabs). X-ray crystallographic characterisation of the hits from a 960-member fragment screen identified three ligand-binding hotspots across the PPAT active site. From the fragment hits a collection of 19F reporter candidates were designed and synthesised. By rigorous prioritisation and use of optimisation workflows, a single 19F reporter molecule was generated for each hotspot. Profiling the binding of a set of structurally characterised ligands by competitive 19F LB-NMR with this suite of 19F reporters recapitulated the binding affinity and site ID assignments made by ITC and X-ray crystallography. This quantitative mapping of ligand binding events at hotspot level resolution establishes the utility of the fragment-based competitive 19F LB-NMR screening platform for hotspot-directed ligand profiling.