title: Synthesis and Pharmacological Evaluation of Novel Adenine-Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Lougiakis
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Gikas
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Toumpas
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Efentakis
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg , 91054 Erlangen, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Wedmann
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.|Second University Department of Cardiology, Medical School, Attikon General Hospital, National and Kapodistrian University of Athens, 12462, Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zoga
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Second University Department of Cardiology, Medical School, Attikon General Hospital, National and Kapodistrian University of Athens, 12462, Athens, Greece.
authors.forename: Efstathios K
authors.initials: EK
authors.lastname: Iliodromitis
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg , 91054 Erlangen, Germany.
authors.forename: Milos R
authors.initials: MR
authors.lastname: Filipovic
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pouli
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Marakos
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771, Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006339:Heart Rate / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D017202:Myocardial Ischemia / Q000188:drug therapy*; D011817:Rabbits
chemical_list: D002316:Cardiotonic Agents; D000225:Adenine; D006862:Hydrogen Sulfide