Zheng Yueqin, Yu Bingchen, Ji Kaili, Pan Zhixiang, Chittavong Vayou, Wang Binghe
Department of Chemistry, Georgia State University, Atlanta, GA, 30303-3083, USA.
Angew Chem Int Ed Engl. 2016 Mar 24;55(14):4514-8. doi: 10.1002/anie.201511244. Epub 2016 Jan 28.
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, H2 S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2 S 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 H2 S 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 H2 S prodrugs shows great potential as both research tools and therapeutic agents.
本文描述了一类前药，这类前药在酯酶介导酯基裂解并随后发生内酯化反应时会释放硫化氢。通过修饰酯基，从而改变其对酯酶的敏感性以及对内酯化速率至关重要的结构特征，可以调节硫化氢的释放速率。此类前药直接释放硫化氢，无需硫醇类物质参与，而硫醇类物质在现有的硫化氢供体中较为常见。此外，此类前药能够轻松地与另一种非甾体抗炎药偶联，从而便于合成杂合前药。作为对硫化氢前药的生物学验证，通过研究一种此类前药抑制RAW 264.7细胞中脂多糖诱导的肿瘤坏死因子-α产生的能力，考察了其抗炎作用。这类硫化氢前药作为研究工具和治疗药物均显示出巨大潜力。
