An Esterase‐Sensitive Prodrug Approach for Controllable Delivery of Persulfide Species

Abstract

A strategy to deliver a well‐defined persulfide species in a biological medium is described. Under near physiological conditions, the persulfide prodrug can be activated by an esterase to generate a “hydroxymethyl persulfide” intermediate, which rapidly collapses to form a defined persulfide. Such persulfide prodrugs can be used either as chemical tools to study persulfide chemistry and biology or for future development as H2S‐based therapeutic reagents. Using the persulfide prodrugs developed in this study, the reactivity between S‐methyl methanethiosulfonate (MMTS) with persulfide was unambiguously demonstrated. Furthermore, a representative prodrug exhibited potent cardioprotective effects in a murine model of myocardial ischemia‐reperfusion (MI/R) injury with a bell shape therapeutic profile.

Self-Immolative Prodrugs: Effective Tools for the Controlled Release of Sulfur Signaling Species

“…Following Galardon's report, Wang and coworkers developed an esterase-sensitive persulfide donor that utilizes an O-to-S relay deprotection mechanism as a means of releasing its persulfide payload (Scheme 2, b). 40 In this work, several ester-methyldisulfide derivatives were synthesized, and strong protective effects from these donors were observed in ischemia/reperfusion (I/R) injury in murine models. Wang then extended this design, developing a prodrug system that releases hydrogen persulfide (H 2 S 2 ).…”

O→S Relay Deprotection: A General Approach to Controllable Donors of Reactive Sulfur Species

“…[15] Enzyme-triggered release of small biologically active molecules is au seful strategy in exploring their biological functions. As shown in Scheme 6, the treatment of 4b and 4e with Ac 2 Ointhe presence of Sc(OTf) 3 as the catalyst led to the formation of the desired O-acetyl persulfide donors 7band 7e,respectively,ingood yields.Compounds like 7b/7e could serve as esterase-triggered persulfide donors.…”

Polymeric Persulfide Prodrugs: Mitigating Oxidative Stress through Controlled Delivery of Reactive Sulfur Species

“…In the time since this initial report, many different types of H 2 S-releasing compounds (termed H 2 S donors) have been synthesized to aid in probing its signaling pathways and to realize its therapeutic potential. Thus far, H 2 S donors with a variety of triggers have been developed, including water, − nucleophiles, , light, , and enzymes. − More recently, donors of related RSS, including carbonyl sulfide (COS), , sulfur dioxide (SO 2 ), − and persulfides (also called perthiols, R–SSH), − have also been developed. All of these donors increase our understanding of the roles that RSS play in a biological context, and some may hold therapeutic value in the form of prodrugs and drug conjugates. , …”

“…Here we aimed to develop polymeric persulfide donors, with the goal of extending their release half-life compared with small molecule persulfide donors and evaluate the biological effects resulting from sustained release. No polymeric persulfide donors have been reported, but currently available small molecule persulfide donors release persulfides in response to a variety of stimuli, including hydrogen peroxide (H 2 O 2 ), esterase activity, pH changes, and addition of F – . − , For example, Wang and co-workers reported an esterase-sensitive persulfide donor that utilized a 1,2-elimination reaction to release its persulfide payload (Scheme a), showing protective effects in myocardial ischemia/reperfusion injury . The same group also recently reported the synthesis and characterization of a G–SSH donor using a trimethyl lock caging group (Scheme b) .…”

“…[29][30][31][32]44 For example, Wang and co-workers reported an esterase-sensitive persulfide donor that utilized a 1,2-elimination reaction to release its persulfide payload (Scheme 1a), showing protective effects in myocardial ischemia/reperfusion injury. 31 The same group also recently reported the synthesis and characterization of a G−SSH donor using a trimethyl lock caging group (Scheme 1b). 45 Our lab recently developed a persulfide donor that responds to H 2 O 2 , utilizing a 1,6-elimination reaction to release N-acetyl cysteine persulfide (NAC−SSH), which rescued H9C2 cardiomyocytes from H 2 O 2 -induced oxidative stress as effectively or more effectively than a number of H 2 S donors.…”