15 research outputs found
Aryl Fluorosulfate Trapped Staudinger Reduction
A chemoselective
Staudinger reduction/sulfurÂ(VI) fluoride exchange
cascade has been developed to join two chemical segments through an
aryl sulfamate ester (RNH–SO<sub>2</sub>–OAr) linkage.
Aryl fluorosulfate is exploited in this work as the first tetrahedral
electrophilic trap for the in situ generated iminophosphorane. Ten
examples using azide-containing compounds are presented
Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides
Sulfur-Fluoride Exchange (SuFEx) is the new generation click chemistry transformation exploiting the unique properties of S-F bonds and their ability to undergo near-perfect reactions with nucleophiles. We report here the first SuFEx based protocol for the efficient synthesis of pharmaceutically important triflones and bis(trifluoromethyl)sulfur oxyimines from the corresponding sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new protocol involves the rapid exchange of the S-F bond with trifluoromethyltrimethylsilane (TMSCF3) upon activation with potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. A tentative catalytic mechanism is proposed supported by DFT calculations, involving formation of the free trifluoromethyl anion followed by nucleophilic displacement of the S-F through a five-coordinate intermediate. The preparation of a benzothiazole derived bis(trifluoromethyl)sulfur oxyimine with cytotoxic selectivity for MCF7 breast cancer cells demonstrates the utility of this methodology for the late-stage functionalization of bioactive molecules
Identification of Styryl Sulfonyl Fluoride (SSF) as An Efficient, Robust and Irreversible Cysteine-specific Protein Bioconjugation Reagent
Cysteine (Cys)-specific bioconjugation has found wide application in the synthesis of protein conjugates, particularly for the functionalization of antibody. Here, through direct assessment on protein substrate, we report the discovery of trans-styryl sulfonyl fluoride (SSF) as a near perfect Michael acceptor (MA) for cysteine-specific protein bioconjugation. Com-pared to predominantly used maleimides, SSF exhibited better chemoselectivity, self-stability and conjugate-stability while kept comparable reactivity. Using SSF-derived probes, proteins can be readily modified on the Cys residue(s) to install functionalities, e.g., fluorescent dyes, toxins and oligonucleotides (oligos), without the influence of activity. Fur-ther applications of SSF derived serum stable antibody-drug conjugates and PD-L1 nanobody-oligo conjugates demon-strate the great translational value of SSF-based bioconjugation in the drug development and single-cell sequencing
Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides
Sulfur-Fluoride
Exchange (SuFEx) is the new generation click chemistry transformation exploiting
the unique properties of S-F bonds and their ability to undergo near-perfect
reactions with nucleophiles. We report here the first SuFEx based protocol for
the efficient synthesis of pharmaceutically important triflones and
bis(trifluoromethyl)sulfur oxyimines from the corresponding sulfonyl fluorides
and iminosulfur oxydifluorides, respectively. The new protocol involves the
rapid exchange of the S-F bond with trifluoromethyltrimethylsilane (TMSCF3)
upon activation with potassium bifluoride in anhydrous DMSO. The reaction
tolerates a wide selection of substrates and proceeds under mild conditions
without need for chromatographic purification. A tentative catalytic mechanism
is proposed supported by DFT calculations, involving formation of the free
trifluoromethyl anion followed by nucleophilic displacement of the S-F through
a five-coordinate intermediate. The preparation of a benzothiazole derived
bis(trifluoromethyl)sulfur oxyimine with cytotoxic selectivity for MCF7 breast
cancer cells demonstrates the utility of this methodology for the late-stage
functionalization of bioactive molecules.<br /
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SuFEx-Based Polysulfonate Formation from Ethenesulfonyl Fluoride-Amine Adducts.
The SuFEx-based polycondensation between bisalkylsulfonyl fluorides (AA monomers) and bisphenol bis(t-butyldimethylsilyl) ethers (BB monomers) using [Ph3 P=N-PPh3 ]+ [HF2 ]- as the catalyst is described. The AA monomers were prepared via the highly reliable Michael addition of ethenesulfonyl fluoride and amines/anilines while the BB monomers were obtained from silylation of bisphenols by t-butyldimethylsilyl chloride. With these reactions, a remarkable diversity of monomeric building blocks was achieved by exploiting readily available amines, anilines, and bisphenols as starting materials. The SuFEx-based polysulfonate formation reaction exhibited excellent efficiency and functional group tolerance, producing polysulfonates with a variety of side chain functionalities in >99 % conversion within 10 min to 1 h. When bearing an orthogonal group on the side chain, the polysulfonates can be further functionalized via click-chemistry-based post-polymerization modification
[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 in vivo tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1)
SuFEx-Enabled High-Throughput Medicinal Chemistry
Optimization of small-molecule probes or drugs is a lengthy, challenging and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible SuFEx click chemistry. A modest high-throughput screening hit against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN=S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products directly screened to yield drug-like inhibitors with 300-fold higher potency. We showed that the improved molecule is drug-like and biologically active in a bacteria-host coculture. Since these reactions can be performed on a picomole scale to conserve reagents, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.</p
"Sleeping Beauty" Phenomenon: SuFEx-Enabled Discovery of Selective 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 approach exploiting the "Sleeping beauty" phenomenon of sulfur fluoride compounds in the context of the serendipitous discovery of selective covalent human neutrophil elastase (hNE) inhibitors. Evaluation of an ever-growing collection of SuFExable compounds toward various biological assays unexpectedly yielded a selective and covalent hNE inhibitor, benzene-1,2-disulfonyl fluoride. Derivatization of the initial hit led to a better agent, 2- triflyl benzenesulfonyl fluoride, itself made through a SuFEx trifluoromethylation process, with IC50 = 1.1 μM and ~200-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized probe only modified active hNE and not its denatured form, setting another example of the "sleeping beauty" phenomenon of sulfur fluoride capturing agents for the discovery of covalent medicines
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Nanomolar Protein Thermal Profiling with Modified Cyanine Dyes.
Protein properties and interactions have been widely investigated by using external labels. However, the micromolar sensitivity of the current dyes limits their applicability due to the high material consumption and assay cost. In response to this challenge, we synthesized a series of cyanine5 (Cy5) dye-based quencher molecules to develop an external dye technique to probe proteins at the nanomolar protein level in a high-throughput one-step assay format. Several families of Cy5 dye-based quenchers with ring and/or side-chain modifications were designed and synthesized by introducing organic small molecules or peptides. Our results showed that steric hindrance and electrostatic interactions are more important than hydrophobicity in the interaction between the luminescent negatively charged europium-chelate-labeled peptide (Eu-probe) and the quencher molecules. The presence of substituents on the quencher indolenine rings reduces their quenching property, whereas the increased positive charge on the indolenine side chain improved the interaction between the quenchers and the luminescent compound. The designed quencher structures entirely altered the dynamics of the Eu-probe (protein-probe) for studying protein stability and interactions, as we were able to reduce the quencher concentration 100-fold. Moreover, the new quencher molecules allowed us to conduct the experiments using neutral buffer conditions, known as the peptide-probe assay. These improvements enabled us to apply the method in a one-step format for nanomolar protein-ligand interaction and protein profiling studies instead of the previously developed two-step protocol. These improvements provide a faster and simpler method with lower material consumption
SuFEx-Based Polysulfonate Formation from Ethenesulfonyl Fluoride-Amine Adducts.
The SuFEx-based polycondensation between bisalkylsulfonyl fluorides (AA monomers) and bisphenol bis(t-butyldimethylsilyl) ethers (BB monomers) using [Ph3 P=N-PPh3 ]+ [HF2 ]- as the catalyst is described. The AA monomers were prepared via the highly reliable Michael addition of ethenesulfonyl fluoride and amines/anilines while the BB monomers were obtained from silylation of bisphenols by t-butyldimethylsilyl chloride. With these reactions, a remarkable diversity of monomeric building blocks was achieved by exploiting readily available amines, anilines, and bisphenols as starting materials. The SuFEx-based polysulfonate formation reaction exhibited excellent efficiency and functional group tolerance, producing polysulfonates with a variety of side chain functionalities in >99 % conversion within 10 min to 1 h. When bearing an orthogonal group on the side chain, the polysulfonates can be further functionalized via click-chemistry-based post-polymerization modification