title: Efficacy of novel acridine derivatives in the inhibition of hPrP90-231 prion protein fragment toxicity.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology and Neuroscience, Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV, 2, 16132 Genoa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Villa
authors.forename: Michele
authors.initials: M
authors.lastname: Tonelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Thellung
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.forename: Bruno
authors.initials: B
authors.lastname: Tasso
authors.forename: Federica
authors.initials: F
authors.lastname: Novelli
authors.forename: Caterina
authors.initials: C
authors.lastname: Canu
authors.forename: Albiana
authors.initials: A
authors.lastname: Pino
authors.forename: Katia
authors.initials: K
authors.lastname: Chiovitti
authors.forename: Domenico
authors.initials: D
authors.lastname: Paludi
authors.forename: Claudio
authors.initials: C
authors.lastname: Russo
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Antonio
authors.initials: A
authors.lastname: Aceto
authors.forename: Vito
authors.initials: V
authors.lastname: Boido
authors.forename: Fabio
authors.initials: F
authors.lastname: Sparatore
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011796:Quinacrine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000166:Acridines; D010446:Peptide Fragments; D011328:Prions; C514520:prion protein (91-231), human; D011796:Quinacrine
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