Substituent Effects Govern the Fidelity of Responsive Persulfide Donors
Abstract
Persulfides (RSSH) are important intermediates in sulfur transfer and trafficking in redox biology, yet the intrinsic chemistry of these molecules complicates the design of small molecule donors that deliver persulfides on demand. Here, we investigate how specific parameters of both the persulfide payload and disulfide structure in selfimmolative donors influence persulfide release, H2S formation, and the susceptibility to degradation by biological thiols. Notably, we demonstrate that many common structures used for persulfide delivery likely do not produce the intended payloads due to a combination of unexpected thiol-disulfide exchange reactions prior to donor activation or subsequent instability of the released persulfide. Using a family of esterase-activated donor constructs, we show that geminal dimethyl substitution at the benzylic position accelerates self-immolative payload release and decreases unwanted thiol-disulfide exchange prior to donor activation. We also establish that steric protection of the release persulfide strongly influences its downstream fate, with unhindered cysteinederived persulfides generating substantially more H2S than sterically protected penicillamine-derived systems. Importantly, thiol exchange studies reveal that insufficiently protected caged disulfides can be consumed rapidly by GSH before trigger activation, thereby diminishing donor integrity. Together, these results establish that the functionality of persulfide donors is governed by steric protection, which influences the competing pathways of donor activation, thiol exchange, persulfide persistence, and H2S formation. More broadly, this work establishes design principles for high-fidelity persulfide delivery and provides a framework for interpreting biological studies in which persulfide donors may participate in competing sulfur transfer and sulfur release pathways.
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BibTeX
@misc{ismail2026substituent,
title = {{Substituent Effects Govern the Fidelity of Responsive Persulfide Donors}},
author = {Ismail Ismail and Michael D. Pluth},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009665/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009665/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Substituent Effects Govern the Fidelity of Responsive Persulfide Donors
AU - Ismail Ismail
AU - Michael D. Pluth
PY - 2026
DA - 2026/09/29
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009665/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009665/v1
AB - Persulfides (RSSH) are important intermediates in sulfur transfer and trafficking in redox biology, yet the intrinsic chemistry of these molecules complicates the design of small molecule donors that deliver persulfides on demand. Here, we investigate how specific parameters of both the persulfide payload and disulfide structure in selfimmolative donors influence persulfide release, H2S formation, and the susceptibility to degradation by biological thiols. Notably, we demonstrate that many common structures used for persulfide delivery likely do not produce the intended payloads due to a combination of unexpected thiol-disulfide exchange reactions prior to donor activation or subsequent instability of the released persulfide. Using a family of esterase-activated donor constructs, we show that geminal dimethyl substitution at the benzylic position accelerates self-immolative payload release and decreases unwanted thiol-disulfide exchange prior to donor activation. We also establish that steric protection of the release persulfide strongly influences its downstream fate, with unhindered cysteinederived persulfides generating substantially more H2S than sterically protected penicillamine-derived systems. Importantly, thiol exchange studies reveal that insufficiently protected caged disulfides can be consumed rapidly by GSH before trigger activation, thereby diminishing donor integrity. Together, these results establish that the functionality of persulfide donors is governed by steric protection, which influences the competing pathways of donor activation, thiol exchange, persulfide persistence, and H2S formation. More broadly, this work establishes design principles for high-fidelity persulfide delivery and provides a framework for interpreting biological studies in which persulfide donors may participate in competing sulfur transfer and sulfur release pathways.
ER -