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Reactivity of 9‐aminoacridine drug quinacrine with glutathione limits its antiprion activity
Author(s) -
Šafařík Martin,
Moško Tibor,
Zawada Zbigniew,
Šafaříková Eva,
Dračínský Martin,
Holada Karel,
Šebestík Jaroslav
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12918
Subject(s) - glutathione , acridone , acridine , chemistry , moiety , bioavailability , conjugate , in vitro , acridine derivatives , drug , biochemistry , pharmacology , stereochemistry , enzyme , biology , organic chemistry , mathematical analysis , mathematics
Quinacrine—the drug based on 9‐aminoacridine—failed in clinical trials for prion diseases, whereas it was active in in vitro studies. We hypothesize that aromatic nucleophilic substitution at C9 could be contributing factor responsible for this failure because of the transfer of acridine moiety from quinacrine to abundant glutathione. Here, we described the semi‐large‐scale synthesis of the acridinylated glutathione and the consequences of its formation on biological and biophysical activities. The acridinylated glutathione is one order of magnitude weaker prion protein binder than the parent quinacrine. Moreover, according to log D pH 7.4 , the glutathione conjugate is two orders of magnitude more hydrophilic than quinacrine. Its higher hydrophilicity and higher ds DNA binding potency will significantly decrease its bioavailability in membrane‐like environment. The glutathione deactivates quinacrine not only directly but also decreases its bioavailability. Furthermore, the conjugate can spontaneously decompose to practically insoluble acridone, which is precipitated out from the living systems.