Esterase‐Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide

Abstract

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2S prodrugs shows great potential as both research tools and therapeutic agents.

Organic CO Prodrugs: Structure–CO‐Release Rate Relationship Studies

“…We have demonstrated this point using another gasotransmitter, hydrogen sulfide. [11] Moreover, it is widely acknowledged that CO-RMs/CO prodrugs with different releasing profiles are required in different biological milieu.…”

“…[7, 11–12] Recently, we have disclosed the first class of CO-prodrugs that can release CO under physiological condition. [12c] Such CO prodrugs can spontaneously release CO upon dissolution in a mixed aqueous solution or in a biological medium, and generate a fluorescent reporter after CO release (Figure 1, Scaffold I).…”

Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

“…The need to develop donors with improved properties for use as research tools and potential therapeutic agents, led to the synthesis of thioaminoacids , arylthioamides (Martelli et al, 2013), N-mercapto (N-SH)-based derivatives (Zhao et al, 2011(Zhao et al, , 2015, 1,2-dithiole-3-thiones (Caliendo et al, 2010), dithioperoxyanhydrides (Roger et al, 2013), and photoinduced (Zheng et al, 2015) and esterasesensitive prodrugs (Zheng et al, 2016) as H 2 S donors. Water solubility, oral bioavailability, an intermediate H 2 S release rate, and generation of H 2 S in a controlled fashion (as, for example, after enzymatic activation), are among the desirable properties of an "ideal" donor.…”

Gasotransmitter delivery via self-assembling peptides: Treating diseases with natural signaling gases

“…Other H 2 S-releasing small molecules, including dithiolethiones [97] and light-triggered H 2 S-releasing compounds such as gem-dithiols and nitrobenzyl thioethers [98,99] have also been reported. Most recently, the first enzyme-triggered H 2 S donor was reported, which uses a trimethyl lock unit to effect H 2 S release upon enzymatic cleavage of an ester [100]. A detailed review of the different release characteristics of H 2 S donors has recently been published [101].…”