Structure–activity relationship study of 9-aminoacridine compounds in scrapie-infected neuroblastoma cells

May, Barnaby C. H.; Witkop, Juanita; Sherrill, John; Anderson, Marc O.; Madrid, Peter B.; Zorn, Julie A.; Prusiner, Stanley B.; Cohen, Fred E.; Guy, R. Kiplin

doi:10.1016/j.bmcl.2006.06.050

Cited by 28 publications

(14 citation statements)

References 18 publications

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“…Investigations into the structure-activity relationships of quinacrine analogues showed that antiprion activity in vitro was greatly influenced by several structural features, namely, the length of the alkyl linker attached to the 9-amino functionality, the substituents on the distal tertiary amino group of the alkyl side chain, and the substitution pattern on the acridine ring (Korth et al 2001;May et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Novel Acridine Derivatives in the Inhibition of hPrP90-231 Prion Protein Fragment Toxicity

et al. 2010

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Quinacrine is one of the few molecules tested to treat patients affected by prion diseases, although the clinical outcome is largely unsatisfactory. To identify novel derivatives with higher neuroprotective activity, we evaluated the effects of a small library of acridine derivatives. The 6-chloro-2-methoxyacridine derivatives bearing on position 9 a quinolizidin-1-ylamino (Q1, Q2) or a quinolizidin-1-ylalkylamino residue (Q3, Q4, Q6, Q7), the thio-bioisoster of Q3 (Q5), the 9-(N-lupinylthiopropyl)amino derivative (Q8) and simple acridines (Q9 and Q10) were considered. We compared the effects of quinacrine and these novel analogues in the inhibition of the cytotoxic activity and protease K (PK) resistance of the human prion protein fragment 90-231 (hPrP90-231). We demonstrate that quinacrine caused a significant reduction of hPrP90-231 toxicity due to its binding to the fragment and the prevention of its conversion in a toxic isoform. All acridine derivatives analyzed showed high affinity binding for hPrP90-231, but only Q3 and Q10, caused a significant reduction of hPrP90-231 cytotoxicity, with higher efficacy than quinacrine. We attempted to correlate the cytoprotective effects of the new compounds with some biochemical parameters (binding affinity to hPrP90-231, intrinsic fluorescence quenching, hydrophobic amino acid exposure), but a direct relationship occurred only with the reduction of PK resistance, likely due to the prevention of the acquisition of the β-sheet-rich toxic conformation. These data represent interesting leads for further modifications of the basic side chain and the substituent pattern of the acridine nucleus to develop novel compounds with improved antiprion activity to be tested in in vivo experimental setting.

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Section: Discussionmentioning

confidence: 99%

Efficacy of Novel Acridine Derivatives in the Inhibition of hPrP90-231 Prion Protein Fragment Toxicity

et al. 2010

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“…First, the effects of "antiprion" compounds are clearly species/strain-dependent, in that drugs found to restrain prions in one situation may improve replicative ability in another. Based on initial reports of quinacrine's effects on mouse prion propagation in cell culture, a plethora of studies were designed to discern the mechanism of its presumed antiprion effects (19,20,(29)(30)(31)(38)(39)(40)(41)(42)(43)(44)(45), to assess its pharmacokinetics (21,36,42,46) and to derive similar compounds with improved antiprion efficacy (18,20,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). These studies continue to this day, despite multiple failed clinical studies in patients with human prion diseases (10)(11)(12)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

Proc. Natl. Acad. Sci. U.S.A.

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Quinacrine's ability to reduce levels of pathogenic prion protein (PrP Sc ) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP Sc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP Sc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP Sc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.prion therapeutics | prion enhancing drugs P rions are protein-based infectious agents that cause an increasing variety of fatal, infectious neurodegenerative disorders, frequently as epidemics. Variant Creutzfeldt-Jakob disease (CJD) resulting from bovine spongiform encephalopathy exemplifies prion zoonosis, and the continued, unpredictable emergence of additional epidemics in other species, particularly chronic wasting disease (CWD) in deer, elk, and moose, raises additional concerns. Its unprecedented contagious spread, widening host range, and conflicting evidence surrounding its zoonotic potential place CWD at the forefront of public health concerns. Although the notion, that prion replication occurs by corruption of host-encoded cellular prion protein (PrP C ) by abnormally conformed PrP Sc , is now widely accepted, the details of this mechanism remain enigmatic.Except under certain experimental conditions, treatments capable of arresting or of effectively modifying the course of disease do not exist for prion disorders. Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1-5) or to confirm the proposed antiprion effects of compounds discovered by other means (6, 7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in ...

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“…As the consequence, the drug can be viewed as potential anti-prion agent and could be applied for treatment of patients with Creutzfeld-Jacobs disease or its new variant [6]. Structureactivity relationship study of derivatives relative to quinacrine was carried out [163]. It indicated that substitution of diethylamino group by di-n-propylamino group, methoxy group by trifluoromethyl group and chloro group by methoxy group led to compounds with activity similar to quinacrine, however, with reduced toxicity.…”

Section: Interaction With Non Nucleic Acid Binding Proteinsmentioning

confidence: 99%

A Role of the 9-Aminoacridines and their Conjugates in a Life Science

Šebestı́k¹,

Hlaváček²,

Stibor

2007

CPPS

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The 9-aminoacridines play an important role in medicine. They were applied first in a treatment of protozoal infections in the beginning of the last century. Recently, it has been shown that the 9-aminoacridines are successful candidates for treatment of cancer, viral and prion diseases. Their conjugation with biomolecules such as peptides and proteins may modulate their activity, bioavailability and applicability. This review deals with the synthesis of 9-aminoacridine, its conjugation with variety of molecules and utilization of such conjugates in several fields of science.

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Structure–activity relationship study of 9-aminoacridine compounds in scrapie-infected neuroblastoma cells

Cited by 28 publications

References 18 publications

Efficacy of Novel Acridine Derivatives in the Inhibition of hPrP90-231 Prion Protein Fragment Toxicity

Efficacy of Novel Acridine Derivatives in the Inhibition of hPrP90-231 Prion Protein Fragment Toxicity

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

A Role of the 9-Aminoacridines and their Conjugates in a Life Science

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