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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00477495" target="_blank" >RIV/61388963:_____/17:00477495 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/17:10364151

Výsledek na webu

<a href="http://dx.doi.org/10.1111/cbdd.12918" target="_blank" >http://dx.doi.org/10.1111/cbdd.12918</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/cbdd.12918" target="_blank" >10.1111/cbdd.12918</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Chemical Biology & Drug Design

ISSN

1747-0277

e-ISSN

—

Svazek periodika

89

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

932-942

Kód UT WoS článku

000405100700011

EID výsledku v databázi Scopus

2-s2.0-85019199825