Šafařík Martin, Moško Tibor, Zawada Zbigniew, Šafaříková Eva, Dračínský Martin, Holada Karel, Šebestík Jaroslav
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic.
First Faculty of Medicine, Institute of Immunology and Microbiology, Charles University in Prague, Prague 2, Czech Republic.
Chem Biol Drug Des. 2017 Jun;89(6):932-942. doi: 10.1111/cbdd.12918. Epub 2017 Jan 25.
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 , 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.
喹吖因——一种基于9-氨基吖啶的药物——在朊病毒疾病的临床试验中失败了，尽管它在体外研究中具有活性。我们推测，由于吖啶部分从喹吖因转移到大量存在的谷胱甘肽，C9位的芳环亲核取代可能是导致这种失败的一个因素。在此，我们描述了吖啶化谷胱甘肽的半大规模合成及其形成对生物和生物物理活性的影响。吖啶化谷胱甘肽与朊病毒蛋白结合的能力比母体喹吖因弱一个数量级。此外，根据分配系数，谷胱甘肽共轭物的亲水性比喹吖因高两个数量级。其更高的亲水性和更高的双链DNA结合能力将显著降低其在膜状环境中的生物利用度。谷胱甘肽不仅直接使喹吖因失活，还降低其生物利用度。此外，共轭物可自发分解为几乎不溶的吖啶酮，从生物系统中沉淀出来。
