Synthesis and Pharmacological Evaluation of Novel Adenine–Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents

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• 作者：Nikolaos Lougiakis ; Andreas Papapetropoulos ; Evangelos Gikas ; Spyridon Toumpas ; Panagiotis Efentakis ; Rudolf Wedmann ; Anastasia Zoga ; Zhongmin Zhou ; Efstathios K. Iliodromitis ; Alexios-Leandros Skaltsounis ; Milos R. Filipovic ; Nicole Pouli ; Panagiotis Marakos ; Ioanna Andreadou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1776-1790
• 全文大小：649K
• ISSN：1520-4804

文摘

This work deals with the design, synthesis, and evaluation of the cardioprotective properties of a number of novel hybrid compounds combining the adenine nucleus with a suitable H<sub>2sub>S slow-releasing moiety, coupled via a stable ether bond. The H<sub>2sub>S release rate of the hybrids and their ability to increase cGMP were estimated in vitro. The most promising derivatives 4 and 11, both containing 4-hydroxythiobenzamide moiety as H<sub>2sub>S donor, were selected for further in vivo evaluation. Their ability to release H<sub>2sub>S in vivo was recorded using a new fully validated UPLC-DAD method. Both compounds reduced significantly the infarct size when administered at the end of sustained ischemia. Mechanistic studies showed that they conferred enhanced cardioprotection compared to adenine or 4-hydroxythiobenzamide. They activate the PKG/PLN pathway in the ischemic myocardium, suggesting that the combination of both pharmacophores results in synergistic cardioprotective activity through the combination of both molecular pathways that trigger cardioprotection.