Role of quinacrine in prion diseases

0446540 - ÚOCHB 2016 BG eng C - Conference Paper (international conference)
Šafařík, Martin - Moško, T. - Zawada, Zbigniew - Dvořáková, E. - Holada, K. - Šebestík, Jaroslav
Role of quinacrine in prion diseases.
Peptides 2014. Proceedings of the Thirty-Third European Peptide Symposium. Sofia: Bulgarian Peptide Society, 2015 - (Naydenova, E.; Pajpanova, T.; Danalev, D.), s. 18-20. ISBN 978-619-90427-2-4.
[Peptides 2014. European Peptide Symposium /33./. Sofia (BG), 31.08.2014-05.09.2014]
R&D Projects: GA ČR(CZ) GA14-00431S
Grant - others:GA ČR(CZ) GAP303/12/1791
Institutional support: RVO:61388963
Keywords : prions * quinacrine * glutathione * acridones * stability
Subject RIV: CC - Organic Chemistry
http://bulpepsoc.info/wp-content/uploads/2015/06/PEPTIDES-2014-electronic-version.pdf

Quinacrine – the member of family of 9-aminoacridines – failed in clinical trials, whereas it showed interesting properties in in-vitro assays. We had previously hypothesized that aromatic nucleophilic substitution at C9 could be responsible for this failure because of the transfer of acridine moiety from quinacrine to abundant glutathione. Here, we describe the scale-up of the synthesis and the consequences of a such displacement on biological and biophysical activities. The acridinylated glutathione is a weaker prion protein binder than parent quinacrine. Moreover, according to log D(pH 7.4) the glutathione conjugate is more hydrophilic than quinacrine. Its higher hydrophilicity and higher dsDNA binding potency will decrease significantly its bioavailability in membrane-like environment. The glutathione deactivates quinacrine not only directly but also decreases its bioavailability. Moreover, with time, the conjugate decomposes to practically insoluble acridone. Thus, in drug design, the new family of 9-aminoacridines should be resistant towards N-S displacement.
Permanent Link: http://hdl.handle.net/11104/0248527