N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release

Abstract

Hydrogen sulfide (H 2 S) is an important biomolecule, and selfimmolative thiocarbamates have shown great promise as triggerable H 2 S donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient H 2 S donors. We report here the synthesis and study of a series of N-methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for H 2 S release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate N-methylation does block some side reactivity and increases the H 2 S release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electronpoor donors is likely due to other side reactions.

Progress and perspective on hydrogen sulfide donors and their biomedical applications

“…Specifically, donors with low p K a values R ‐ NH 2 have a relatively faster H 2 S‐releasing rate than the donors with high p K a values R ‐ NH 2 . From the electronic effects point of view, the results obtained from this study might also be explained by the most recent work of Pluth' group 111 . The tunable H 2 S‐releasing properties and a well‐defined mechanism of carbamothioate‐based COS/H 2 S donors make donor 65 has superior advantages over other types of COS/H 2 S donors.…”

“…The kinetic experimental results showed that the thiocarbamate‐based donor 59 with R = EDGs were fast and potent H 2 S donors, whereas with R = EWGs were slow and poor H 2 S donors. The mechanisms underlying this experimental fact might be explained by the most recent work of Pluth's group, 111 although the authors of this study proposed another isothiocyanate‐generating mechanism. Donor 60 was rather unstable in solution (probably owing to the existence of a thioester group) and toward ROS (demonstrated by using a model compound without arylboronate trigger; the statement about stability toward ROS in the following part is conducted using model compounds without arylboronate trigger), and thus they released less H 2 S in a slow rate.…”

“…The kinetic experimental results showed that the thiocarbamate-based donor 59 with R = EDGs were fast and potent H 2 S donors, whereas with R = EWGs were slow and poor H 2 S donors. The mechanisms underlying this experimental fact might be explained by the most recent work of Pluth's group, 111 8B, in blue arrow) due to the deprotonation of the N-H bond.…”

“…Most recently, Pluth et al designed four classes of esterase‐sensitive H 2 S donors with thiocarbamate skeleton as their payload (donors 53 , 54 , 55 , and 56 , Figure 7G). 111 Their work aimed to unveil the reason why H 2 S donors (donors 55 ) with electron‐withdrawing groups (EWGs) on the payload are less efficient in release of H 2 S compared with their electron‐donating groups (EDGs)‐containing congeners (donors 56 ). The authors proposed the mechanism of the nonproductive pathway as Figure 7G (shown in red), that is, after removal of pivalic acid group by esterase, deprotonation of N ‐ H bond results in the release of isothiocyanate, an inefficient H 2 S donor.…”

“…On this ground, H 2 S‐releasing agents (also named H 2 S donors) seem to be adequate for either mimicking the endogenous H 2 S generation under physiological conditions, or replenishing additional H 2 S for both diagnostic and therapeutical purposes. During the past years, substantial endeavor has been made to develop various H 2 S donors, and a number of H 2 S donors with different releasing rates and mechanisms have been reported 101,105–125 . H 2 S donors, regarded as the exogenous suppliers of H 2 S, could be employed as the ideal candidates for the treatment of diseases whose H 2 S‐associated networks might be short‐circuited.…”