Nucleophilic substitution reactions of cyclic thiosulfinates are accelerated by hyperconjugative interactions

Donnelly, Daniel P.; Agar, Jeffrey N.; Lopez, Steven A.

doi:10.1039/c9sc01098j

Cited by 10 publications

(10 citation statements)

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“…In addition, cyclic thiosulfinates have nearly 100-fold increased reaction rates as compared to cyclic disulfides (and, by analogy, other disulfide forming chemistries). Finally, the loss of water in the second step provides a relatively large driving force as compared to other cross-linkers . Given their reduced toxicity as compared to other cross-linkers, as well as increased speed as compared to oxidative disulfide formation from thiols, we hypothesized cyclic thiosulfinates could be applied to polymer chemistry.…”

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confidence: 92%

“…Finally, the loss of water in the second step provides a relatively large driving force as compared to other cross-linkers. 43 Given their reduced toxicity as compared to other cross-linkers, as well as increased speed as compared to oxidative disulfide formation from thiols, we hypothesized cyclic thiosulfinates could be applied to polymer chemistry. In this Article, we use both four-arm PEG thiol and thiol-functionalized hyaluronic acid as monomers.…”

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confidence: 93%

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Cyclic Thiosulfinates as a Novel Class of Disulfide Cleavable Cross-Linkers for Rapid Hydrogel Synthesis

et al. 2021

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We recently reported that cyclic thiosulfinates are cysteine selective cross-linkers that avoid the “dead-end” modifications that contribute to other cross-linkers’ toxicity. In this study, we generalize the chemistry of cyclic thiosulfinates to that of thiol selective cross-linking and apply them to the synthesis of hydrogels. Thiol-functionalized four-arm poly(ethylene glycol) and hyaluronic acid monomers were cross-linked with 1,2-dithiane-1-oxide to form disulfide cross-linked hydrogels within seconds. The synthesized hydrogel could be reduced with physiological concentrations of glutathione, which modulated hydrogel mechanical properties and degradation kinetics. Bovine serum albumin protein was successfully encapsulated in hydrogel, and diffusion-mediated release was demonstrated in vitro. Hep G2 cells grew in the presence of preformed hydrogel and during hydrogel synthesis, demonstrating acceptable cytotoxicity. We encapsulated cells within a hydrogel and demonstrated cell growth and recovery up to 10 days, with and without cell adhesion peptides. In summary, we report cyclic thiosulfinates as a novel class of cross-linkers for the facile synthesis of biodegradable hydrogels.

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confidence: 93%

Cyclic Thiosulfinates as a Novel Class of Disulfide Cleavable Cross-Linkers for Rapid Hydrogel Synthesis

et al. 2021

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“…Cyclic thiosulfinates 38 have been shown to selectively target neighboring thiols (D), yielding, through a sulfenate intermediate (E), two disulfide bridges 45 between the cell and substrate (F, Figure 9c). 137,138 The opening of cyclic thiosulfonate substrates 6 with exofacial thiols (G) affords intermediate 46 with one disulfide bridge plus one proximal sulfinate in the substrate, which can continue to exchange with an exofacial disulfide (H, Figure 9d). 139 The net result of the full cascade is the consumption of one exofacial thiol and one disulfide, yielding macrocycle 47 with one disulfide and one thiosulfonate bridge from substrate to cell plus one new exofacial thiol (I, Figure 9d).…”

Section: Extreme Sulfur Chemistry 131mentioning

confidence: 99%

“…Reactivity toward thiols increases with every oxygen added. Cyclic thiosulfinates 38 have been shown to selectively target neighboring thiols ( D ), yielding, through a sulfenate intermediate ( E ), two disulfide bridges 45 between the cell and substrate ( F , Figure c). , …”

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confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

111

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This Perspective focuses on thiol-mediated uptake, that is, the entry of substrates into cells enabled by oligochalcogenides or mimics, often disulfides, and inhibited by thiol-reactive agents. A short chronology from the initial observations in 1990 until today is followed by a summary of cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs) as privileged scaffolds in thiol-mediated uptake and inhibitors of thiol-mediated uptake as potential antivirals. In the spirit of a Perspective, the main part brings together topics that possibly could help to explain how thiol-mediated uptake really works. Extreme sulfur chemistry mostly related to COCs and their mimics, cyclic disulfides, thiosulfinates/-onates, diselenolanes, benzopolysulfanes, but also arsenics and Michael acceptors, is viewed in the context of acidity, ring tension, exchange cascades, adaptive networks, exchange affinity columns, molecular walkers, ring-opening polymerizations, and templated polymerizations. Micellar pores (or lipid ion channels) are considered, from cell-penetrating peptides and natural antibiotics to voltage sensors, and a concise gallery of membrane proteins, as possible targets of thiol-mediated uptake, is provided, including CLIC1, a thiol-reactive chloride channel; TMEM16F, a Ca-activated scramblase; EGFR, the epithelial growth factor receptor; and protein-disulfide isomerase, known from HIV entry or the transferrin receptor, a top hit in proteomics and recently identified in the cellular entry of SARS-CoV-2.

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“…An electron rich nucleophile attacks a positively charged electrophile to replace the lone pair of electrons of the leaving group, so that a new bond is formed. [32] Scheme 3 illustrates a range of nucleophilic substitution reactions on 3bromoacetylcoumarin yielding products displaying various biological activities. For instance, the reaction of 3-bromoacetylcoumarin (2) with heterocyclic amines under reflux conditions formed amino acetyl compounds (3) in good yields.…”

Section: Nucleophilic Substitutions Of 3-bromoacetylcoumarinmentioning

confidence: 99%

3‐Bromoacetylcoumarin, a Crucial Key for Facial Synthesis of Biological Active Compounds

et al. 2022

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Compounds containing the coumarin scaffold are widely used in the pharmaceutical and medicinal industries. The biological activities of coumarin containing derivatives make the attractive for the develop new drugs. Different methods and techniques are developed to synthesize new drugs using coumarin as a starting material. This review summarized various methods, techniques and reaction conditions for synthesis of coumarins containing compounds from 3‐bromoacetylcoumarin. A total of 79 coumarin intermediates and products are reported herein. The different reactions include nucleophilic substitutions, one‐pot and multi‐step synthesis for preparation of coumarin containing compounds through different mechanisms and the outcomes achieved through such reactions are discussed. The prepared compounds showed a range of activities resulting in antifungal, antimicrobial, anti‐inflammatory, antidiabetic and cholinesterase inhibitors. The nucleophilic substitution reactions involving urea related compounds, followed by intramolecular cyclization lead to imidazole and thiazole moieties, which exhibit antibacterial activities. It is hoped that this review provides useful insight for researchers engaged in this field to expand the knowledge gained in this area.

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Nucleophilic substitution reactions of cyclic thiosulfinates are accelerated by hyperconjugative interactions

Abstract: Cyclic thiosulfinates are a class of biocompatible molecules, currently expanding our in vivo toolkit.

Cited by 10 publications

References 48 publications

Cyclic Thiosulfinates as a Novel Class of Disulfide Cleavable Cross-Linkers for Rapid Hydrogel Synthesis

Cyclic Thiosulfinates as a Novel Class of Disulfide Cleavable Cross-Linkers for Rapid Hydrogel Synthesis

Thiol-Mediated Uptake

3‐Bromoacetylcoumarin, a Crucial Key for Facial Synthesis of Biological Active Compounds

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