Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides

Zhou, Hua; Mukherjee, Paramita; Liu, Rongqiang; Evrard, Edelweiss; Wang, Dianpeng; Humphrey, John M.; Butler, Todd W.; Hoth, Lise R.; Sperry, Jeffrey B.; Sakata, Sylvie K.; Helal, Christopher J.; Ende, Christopher W. am

doi:10.1021/acs.orglett.7b03950

Cited by 106 publications

(96 citation statements)

References 35 publications

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“…[44] Considering the feasibility and safety of practical operation and the characteristic of small reaction scale of on-DNA synthesis, we chose solid reagents [4-(acetylamino)phenyl] imidodisulfuryl difluoride (AISF) [45] and fluorosulfuryl imidazolium salt [46] that had recently developed by scientists at Bio-Duro/Pfizer, and the Dong group, respectively, for the on-DNA synthesis of ArOSO 2 F. The results of comparative trials suggested that AISF was a more suitable reagent for the current on-DNA -SO 2 F decoration (see Table S1, Supporting Information). [44] Considering the feasibility and safety of practical operation and the characteristic of small reaction scale of on-DNA synthesis, we chose solid reagents [4-(acetylamino)phenyl] imidodisulfuryl difluoride (AISF) [45] and fluorosulfuryl imidazolium salt [46] that had recently developed by scientists at Bio-Duro/Pfizer, and the Dong group, respectively, for the on-DNA synthesis of ArOSO 2 F. The results of comparative trials suggested that AISF was a more suitable reagent for the current on-DNA -SO 2 F decoration (see Table S1, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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are encoded by unique DNA sequences as identification "barcodes," and are assembled combinatorial using split-andpool strategy or alternative procedures via DNA-compatible reactions. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. [10,11] To date, a large number of high-quality hits have been identified by the DEL technology for various therapeutically relevant targets, such as kinases, [12] phosphatases, [13] and G-protein coupled receptors. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.Despite these successes, the great potential of DEL technology in drug discovery has not yet been fully realized. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. However, the environmental toxicity and high costs of aryl halides have hindered their large-scale applications in industry. Thus, much attention has been paid to phenol-derived electrophiles recently, [27] which, as compared to aryl halides, offer a more sustainable starting material because most of them are readily available from biomass. [28] In addition, phenol modules are also important components of natural products (NPs), bioactive molecules, and pharmaceutical drugs. Coupling reactions with Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp 2 )-C(sp 2 ), C(sp 2 )-C(sp), and C(s...

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Section: Resultsmentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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“…Likewise, the reaction with bromomethyl-benzenesulfonyl fluorides will result in agents as reported in Figure 1B. The synthesis of aryl-fluoro sulfates followed a recently developed approach that takes advantage of the [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF) 37 reagent for the insertion of the fluoro sulfate functional group into Tyr or homo-Tyr ( Figure 1C). Alternatively, substituted or unsubstituted phenol carboxylic acids can be introduced in the side chains of Dap, Dab, Orn, or Lys, and subsequently the phenols can be converted to their corresponding aryl-fluoro sulfates ( Figure 1D) using the same procedure as reported in Figure 1C.…”

Section: Synthesis Of Peptide Mimetics Containing Aryl-mentioning

confidence: 99%

Covalent Inhibitors of Protein–Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues

et al. 2019

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We have recently reported a series of Lys-covalent agents targeting the BIR3 domain of the X-linked inhibitor of apoptosis protein (XIAP) using a benzamide-sulfonyl fluoride warhead. Using XIAP as a model system, we further investigated a variety of additional warheads that can be easily incorporated into binding peptides and analyzed their ability to form covalent adducts with lysine and other amino acids, including tyrosine, histidine, serine, and threonine, using biochemical and biophysical assays. Moreover, we tested aqueous, plasma stability, cell permeability, and cellular efficacy of the most effective agents. These studies identified aryl-fluoro sulfates as likely the most suitable electrophiles to effectively form covalent adducts with Lys, Tyr, and His residues, given that these agents were cell permeable and stable in aqueous buffer and in plasma. Our studies contain a number of general findings that open new possible avenues for the design of potent covalent protein−protein interaction antagonists.

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“…Over the past 5 y, we (1,5,8,56) and others (12,(57)(58)(59)(60) have found a collection of efficient methods to synthesize SuFExable compounds from either simple or complex organic molecules using highly connective SuFEx core electrophiles (e.g., SO 2 F 2 , O = SF 4 , CH 2 = CHSO 2 F). Collective work within the Sharpless laboratory continues to build a library of SuFExable small modules.…”

Section: Significancementioning

confidence: 99%

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

Zheng

Woehl

Kitamura

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

146

136

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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.

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Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides

Cited by 106 publications

References 35 publications

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Covalent Inhibitors of Protein–Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues

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

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