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Chem Biol Drug Des. 2017 Jun;89(6):932-942. doi: 10.1111/cbdd.12918. Epub 2017 Jan 25.

Reactivity of 9-aminoacridine drug quinacrine with glutathione limits its antiprion activity.

Author information

1
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic.
2
First Faculty of Medicine, Institute of Immunology and Microbiology, Charles University in Prague, Prague 2, Czech Republic.

Abstract

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 DpH 7.4 , the glutathione conjugate is two orders of magnitude more hydrophilic than quinacrine. Its higher hydrophilicity and higher dsDNA 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.

KEYWORDS:

antiprion activity; failure in clinical trials; nucleophilic displacement; prion protein binding; quinacrine

PMID:
27933730
DOI:
10.1111/cbdd.12918
[Indexed for MEDLINE]

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