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

• Published in: Angewandte Chemie International Edition 2016-03, Vol.55 (14), p.4514-4518
• Main Authors: Zheng, Yueqin, Yu, Bingchen, Ji, Kaili, Pan, Zhixiang, Chittavong, Vayou, Wang, Binghe
• Format: Article
• Language: English
• Subjects: anti-inflammatory drugs; enzyme trigger; Esterases - chemistry; H2S-NSAIDs; Hydrogen Sulfide - chemical synthesis; Hydrogen Sulfide - chemistry; Hydrogen Sulfide - pharmacokinetics; hydrogen sulfide prodrugs; lactonization; Prodrugs - chemistry
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201511244

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. Tunable H2S supply: Prodrugs that release hydrogen sulfide upon esterase‐mediated cleavage of an ester group followed by lactonization are described (see example). By modifying the ester group and thus its susceptibility to esterase H2S release rates can be tuned. The anti‐inflammatory effects of one candidate were examined by studying its ability to inhibit TNF‐α production in RAW 264.7 cells.