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

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. S...

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Bibliographic Details
Published in:Angewandte Chemie 2016-03, Vol.128 (14), p.4590-4594
Main Authors: Zheng, Yueqin, Yu, Bingchen, Ji, Kaili, Pan, Zhixiang, Chittavong, Vayou, Wang, Binghe
Format: Article
Language:English
Subjects:
Chemical compounds
Chemistry
Cleavage
Drugs
Entzündungshemmer
Enzym-Trigger
Esters
H2S-NSAIDs
H2S-Prodrugs
Hydrogen sulfide
Lactonisierung
Pharmacology
Reagents
Synthesis
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Summary: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. H2S‐Depot: Neuartige Prodrugs wurden entwickelt, die Schwefelwasserstoff durch Esterase‐vermittelte Spaltung einer Estergruppe und anschließende Lactonisierung freisetzen (siehe Beispiel). Durch Modifizierung der Estergruppe und damit der Esterase‐Reaktivität kann die Geschwindigkeit der H2S‐Freisetzung justiert werden. Die entzündungshemmende Wirkung eines der Prodrugs wurde anhand der Inbihition der TNF‐α‐Produktion in RAW264.7‐Zellen untersucht.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201511244