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

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Minocycline Prevents Morphine-Induced Apoptosis in Rat Cerebral Cortex and Lumbar Spinal Cord: A Possible Mechanism for Attenuating Morphine Tolerance

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

Content Provider	Springer Nature Link
Author	Villa, Valentina Tonelli, Michele Thellung, Stefano Corsaro, Alessandro Tasso, Bruno Novelli, Federica Canu, Caterina Pino, Albiana Chiovitti, Katia Paludi, Domenico Russo, Claudio Sparatore, Anna Aceto, Antonio Boido, Vito Sparatore, Fabio Florio, Tullio
Copyright Year	2010
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.
Starting Page	556
Ending Page	574
Page Count	19
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	19
Issue Number	4
e-ISSN	14763524
Language	English
Publisher	Springer-Verlag
Publisher Date	2010-04-20
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Prion protein Quinacrine Quinolizidine derivatives PK resistance Neurotoxicity Neurosciences Pharmacology/Toxicology Neurobiology Cell Biology Neurochemistry Neurology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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Dual Modulation of ERK1/2 and p38 MAP Kinase Activities Induced by Minocycline Reverses the Neurotoxic Effects of the Prion Protein Fragment 90–231

Excitotoxicity Through NMDA Receptors Mediates Cerebellar Granule Neuron Apoptosis Induced by Prion Protein 90-231 Fragment

Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90–231 Neurotoxic Effects in Cerebellar Granule Neurons

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

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Dual Modulation of ERK1/2 and p38 MAP Kinase Activities Induced by Minocycline Reverses the Neurotoxic Effects of the Prion Protein Fragment 90–231

Excitotoxicity Through NMDA Receptors Mediates Cerebellar Granule Neuron Apoptosis Induced by Prion Protein 90-231 Fragment

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