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

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

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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 H2S slow-releasing moiety, coupled via a stable ether bond. The H2S 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 H2S donor, were selected for further in vivo evaluation. Their ability to release H2S 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.

Original languageEnglish (US)
Pages (from-to)1776-1790
Number of pages15
JournalJournal of Medicinal Chemistry
Volume59
Issue number5
DOIs
StatePublished - Mar 10 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Lougiakis, N., Papapetropoulos, A., Gikas, E., Toumpas, S., Efentakis, P., Wedmann, R., Zoga, A., Zhou, Z., Iliodromitis, E. K., Skaltsounis, A. L., Filipovic, M. R., Pouli, N., Marakos, P., & Andreadou, I. (2016). Synthesis and Pharmacological Evaluation of Novel Adenine-Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents. Journal of Medicinal Chemistry, 59(5), 1776-1790. https://doi.org/10.1021/acs.jmedchem.5b01223