Reactivity of 9‐aminoacridine drug quinacrine with glutathione limits its antiprion activity. (25th January 2017)

• Record Type: Journal Article
• Authors: Šafařík, Martin; Moško, Tibor; Zawada, Zbigniew; Šafaříková, Eva; Dračínský, Martin; Holada, Karel; Šebestík, Jaroslav
• Is Part Of: Chemical biology & drug design. Volume 89:Number 6(2017)
• Page Start: 932
• Page End: 942
• Publication Date: 2017-01-25
• Subjects: antiprion activity -- failure in clinical trials -- nucleophilic displacement -- prion protein binding -- quinacrine; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12918
• Languages: English
• ISSNs: 1747-0277

Abstract

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 D pH 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. Abstract : Conjugation of quinacrine with glutathione reduces its antiprion activity, which is even enhanced by catalytic decomposition of the conjugate to practically insoluble acridone.