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

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 , 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.

Solubility of Mono‐Aminoacridines

“…Solubility is important for MALDI‐MS process, where obtaining a homogenous solution of sample and matrix compound is needed for producing high‐quality mass spectra [19–21] . The most used of the isomers, 9‐AA, also finds applications as an intracellular pH indicator, [22] topical antiseptic, [23] fluorescent dye, [24] and drug precursor [25–27] . The other AAs have been used less widely, [17,18] but the aminoacridine moiety itself is part of several dyes, such as acridine yellow and acridine orange.…”

“…[19][20][21] The most used of the isomers, 9-AA, also finds applications as an intracellular pH indicator, [22] topical antiseptic, [23] fluorescent dye, [24] and drug precursor. [25][26][27] The other AAs have been used less widely, [17,18] but the aminoacridine moiety itself is part of several dyes, such as acridine yellow and acridine orange. To the best of our knowledge, there is no work dedicated to the solubility of the AA isomers or closely related compounds.…”