5 Sulfur Fluoride Exchange (SuFEx)

Sulfur Fluoride Exchange (SuFEx) click chemistry is a new generation technology for creating stable molecular connections with absolute reliability under metal-free conditions. SuFEx builds upon the fundamental principles of click chemistry by exploiting a unique blend of stability and latent reactivity of high oxidation state sulfur fluoride [e.g., S(VI)] functionalities to forge stable covalent linkages at connective SuFEx hubs. In this review, we focus mainly on the SuFEx hubs, sulfuryl fluoride (SO2F2), thionyl tetrafluoride (SOF4), ethenesulfonyl fluoride (ESF), 1-bromoethene-1-sulfonyl fluoride (BESF) and, 2-substituted alkyne-1-sulfonyl fluorides (SASFs). We describe each connector’s unique reactivity and their application to SuFEx click chemistry.

Identification of simple arylfluorosulfates as potent agents against resistant bacteria

Sulfur fluoride exchange (SuFEx), a next generation of click chemistry, opens an avenue for drug discovery. We report here the discovery and structure–activity relationship studies of a series of arylfluorosulfates, synthesized via SuFEx, as antibacterial agents. Arylfluorosulfates 3, 81, and 101 showed potency to overcome multidrug resistance and were not susceptible to the generation of resistance. They exhibited rapid bactericidal potency and selectively killed gram-positive bacterial strains. These compounds also exhibited the ability to disrupt established bacterial biofilm and kill persisters derived from biofilm. Furthermore, arylfluorosulfate 3 had a synergistic effect with streptomycin and gentamicin. In addition, their anti-MRSA potency was evaluated and determined by the Caenorhabditis elegans model.

Sulfur(VI) Fluoride Exchange (SuFEx)-Mediated Synthesis of the Chitosan-PEG Conjugate and Its Supramolecular Hydrogels for Protein Delivery

Supramolecular hydrogels are considered promising drug carriers in the tissue engineering field due to their versatile nature. Chitosan hydrogels without chemical cross-linkers have low cytotoxicity and good delivery capacity; however, they have lower mechanical properties for injectable hydrogel usage. In this study, we developed novel chitosan derivatives via click chemistry for fabricating supramolecular hydrogels with higher mechanical strength under mild conditions. The chitosan derivative was successfully synthesized by a sulfur fluoride exchange reaction, and the synthesized chitosan-mPEG/Pluronic-F127 (CS-mPEG/F127) interacted with α-cyclodextrin (α-CD) to form a supramolecular hydrogel via a host-guest reaction. The gelation dynamics, hydrogel properties, and bovine serum albumin (BSA) release could be modulated by the concentration ratio of chitosan-mPEG and F127. This supramolecular hydrogel is a promising protein releasing carrier candidate for long term regeneration therapy.

[18F]SuFEx Click Chemistry Enabled Ultrafast Late-stage Radiosynthesis

The lack of simple, efficient [¹⁸F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [¹⁸F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated ¹⁸F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol^–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [¹⁸F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

[18F]SuFEx Click Chemistry Enabled Ultrafast Late-stage Radiosynthesis

The lack of simple, efficient [¹⁸F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [¹⁸F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated ¹⁸F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol^–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [¹⁸F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

Plasma Etching Behavior of SF6 Plasma Pre-Treatment Sputter-Deposited Yttrium Oxide Films

Yttrium oxyfluoride (YOF) protective materials were fabricated on sputter-deposited yttrium oxide (Y2O3) by high-density (sulfur fluoride) SF6 plasma irradiation. The structures, compositions, and fluorocarbon-plasma etching behaviors of these films were systematically characterized by various techniques. After exposure to SF6 plasma, the Y2O3 film surface was fluorinated significantly to form a YOF film with an approximate average thickness of 30 nm. X-ray photoelectron spectroscopy revealed few changes in the elemental and chemical compositions of the surface layer after fluorination, confirming the chemical stability of the YOF/Y2O3 sample. Transmission electron microscopy confirmed a complete lattice pattern on the YOF/Y2O3 structure after fluorocarbon plasma exposure. These results indicate that the SF6 plasma-treated Y2O3 film is more erosion resistant than the commercial Y2O3 coating, and thus accumulates fewer contamination particles.

Selected Research Topics of the Dondoni Group over the Last Two Decades (2000–2020)

From a selection of research topics carried out in our laboratory during the last twenty years it becomes apparent that our main target was the discovery of new or improved synthetic methods together with new properties. Our efforts were made with the aim of being of some utility to other fields of research, with particular emphasis to glycobiology and heterocyle-based bioorganic chemistry. We performed new chemistry mainly in the field of carbohydrate manipulations taking as a primary rule the simplicity and efficiency manners. Toward this end, modern synthetic tools and approaches were employed such as heterocyle-based transformations, multicomponent reactions, organocatalysis, click azide–alkyne cycloadditions, reactions in ionic liquids, click photoinduced thiol-ene coupling, and click sulfur–fluoride exchange chemistry. With these potent methodologies in hand, the syntheses of carbohydrate containing amino acids up to proteins glycosylation were performed.1 Heterocyclic Glycoconjugates and Amino Acids2 Triazole-Linked Oligonucleotides: Application of Click CuAAC3 Non-Natural Glycosyl Amino Acids4 Non-Natural Oligosaccharides5 Calixarene-Based Glycoclusters6 Carbohydrate-Based Building Blocks7 Homoazasugars and Aza-C-disaccharides8 Synthesis of Glycodendrimers9 Peptide and Protein Glycoconjugates10 Conclusions

Click Chemistry Expedited Radiosynthesis: Sulfur [18F]fluoride Exchange of Aryl Fluorosulfates

The lack of simple, efficient [¹⁸F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [¹⁸F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated ¹⁸F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol^–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [¹⁸F]fluorosulfate is demonstrated by the <i>in vivo</i> tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Sulfur fluoride exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled, agnostic approach for the discovery and optimization of covalent inhibitors of human neutrophil elastase (hNE). Evaluation of our ever-growing collection of SuFExable compounds toward various biological assays unexpectedly revealed a selective and covalent hNE inhibitor: benzene-1,2-disulfonyl fluoride. Synthetic derivatization of the initial hit led to a more potent agent, 2-(fluorosulfonyl)phenyl fluorosulfate with IC50 0.24 μM and greater than 833-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized, yet simple benzenoid probe only modified active hNE and not its denatured form.