Development of Acid-Mediated H<sub>2</sub>S/COS Donors That Respond to a Specific pH Window

Gilbert, Annie; Zhao, Yu; Otteson, Claire E.; Pluth, Michael D.

doi:10.1021/acs.joc.9b01873

Cited by 42 publications

(28 citation statements)

References 35 publications

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“… 12 This feature is exploited during the synthesis of cyclisation–elimination self-immolative polymers 14 and, most recently, for tuning the initial release kinetics of a self-immolative H 2 S delivery agent. 15 However, to the best of our knowledge there are no studies that use transient changes in acidity to dynamically switch a self-immolative linker between active and dormant states following trigger removal. Herein we investigate triazole-based self-immolative linkers that can be reversibly paused or slowed and restarted throughout their self-immolation sequences upon addition of acid and base to the reaction medium.…”

Section: Introductionmentioning

confidence: 99%

Dynamic pH responsivity of triazole-based self-immolative linkers

et al. 2020

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Gating the release of chemical payloads in response to transient signals is an important feature of 'smart' delivery systems. Herein, we report a triazole-based self-immolative linker that can be reversibly paused or slowed and restarted throughout its elimination cascade in response to pH changes in both organic and organic-aqueous solvents. The linker is conveniently prepared using the alkyne-azide cycloaddition reaction, which introduces a 1,4-triazole ring that expresses a pH-sensitive intermediate during its elimination sequence. Using a series of model compounds, we demonstrate that this intermediate can be switched between active and dormant states depending on the presence of acid or base, cleanly gating the release of payload in response to a fluctuating external stimulus.

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Section: Introductionmentioning

confidence: 99%

Dynamic pH responsivity of triazole-based self-immolative linkers

et al. 2020

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“…Deuterated solvents were purchased from Cambridge Isotope Laboratories and used as received. 1 H, 13 C{ 1 H}, and 19 FNMR spectra were recorded on a Bruker 500 MHz instrument. Chemical shifts were reported relative to residual protic solvent resonances.…”

Section: Synthesis Materials and Methodsmentioning

confidence: 99%

“…[16] In our initial approach, we were inspired by self-immolative carbamates, which releaseC O 2 as ab yproduct upon activation, [17] and developed analogouss elf-immolative thiocarbamates that function as tunable COS-based H 2 S donors ( Figure 1a). [18] The high modularity of self-immolative COS-releasing motifs has enabled the rapid expansion of this approach by our group [9] as well as others to prepareC OS-based H 2 Sd onors activated by variouss timuli including acidic pH, [19] esterases, [20] reactive oxygen species, [21] and cysteine. [22] This approach has also been extendedt op rovide oligomeric COS-based H 2 S donors.…”

Section: Introductionmentioning

confidence: 99%

Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

Cerda¹,

Mancuso²,

Mullen³

et al. 2019

Preprint

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The enzymatic conversiono fc arbonyl sulfide (COS) to hydrogen sulfide (H 2 S) by carbonic anhydrase has been used to develops elf-immolatingt hiocarbamates as COS-based H 2 Sd onors to furthere lucidatet he impact of reactive sulfur speciesi nb iology.T he highm odularity of this approach has providedalibrary of COS-based H 2 Sd onors that can be activated by specific stimuli.Acommonl imitation, however,i st hat many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation. As am ilda lternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H 2 Sd onor motifs, and that these groups release two equivalents of COS/H 2 Sa nd uncage an amine payload under physiologically relevant conditions. Additionally,w ed emonstrate that COS/H 2 Sr elease from this donorm otif can be altered by electronic modulationa nd alkyl substitution. These insights are further supported by DFT investigations,w hich reveal that aryl and alkyl thiocarbamates releaseC OS with significantly different activation energies.[a] M.[**] Ap revious versiono ft his manuscript has been deposited on ap reprint server (https://doi.org/10.26434/chemrxiv.11356703.v1).Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.Figure 4. Potential energy surface for COS release from PhDTS and AlkylDTS compounds. Calculations were performedusing Gaussian 09 at the B3LYP/6-311 ++G(d,p)l evel of theory applying the IEF-PCM water solvation model. MeSH was used as the thiol nucleophile to simplify accessibleprotonation states of non-participating functional groupso nt he thiol nucleophile.

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“…The high modularity of self‐immolative COS‐releasing motifs has enabled the rapid expansion of this approach by our group as well as others to prepare COS‐based H 2 S donors activated by various stimuli including acidic pH, esterases, reactive oxygen species, and cysteine . This approach has also been extended to provide oligomeric COS‐based H 2 S donors .…”

Section: Introductionmentioning

confidence: 99%

Use of Dithiasuccinoyl‐Caged Amines Enables COS/H₂S Release Lacking Electrophilic Byproducts

Cerda

Mancuso

Mullen

et al. 2020

Chemistry A European J

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The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H2S) by carbonic anhydrase has been used to develop self‐immolating thiocarbamates as COS‐based H2S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS‐based H2S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H2S donor motifs, and that these groups release two equivalents of COS/H2S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H2S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.

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Development of Acid-Mediated H₂S/COS Donors That Respond to a Specific pH Window

Cited by 42 publications

References 35 publications

Dynamic pH responsivity of triazole-based self-immolative linkers

Dynamic pH responsivity of triazole-based self-immolative linkers

Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

Use of Dithiasuccinoyl‐Caged Amines Enables COS/H₂S Release Lacking Electrophilic Byproducts

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Development of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window

Cited by 42 publications

References 35 publications

Dynamic pH responsivity of triazole-based self-immolative linkers

Dynamic pH responsivity of triazole-based self-immolative linkers

Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

Use of Dithiasuccinoyl‐Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

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Development of Acid-Mediated H₂S/COS Donors That Respond to a Specific pH Window

Use of Dithiasuccinoyl‐Caged Amines Enables COS/H₂S Release Lacking Electrophilic Byproducts