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.

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

“…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).…”

Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer’s disease

“…Finally the aminocompound was reacted with 6,9-dichloro-2-methoxyacridine (Scheme 3). The quinacrine analog 43 [42] has been reprepared according to the described procedure [42], but it was obtained as crystals instead of an oil and in quite higher yield.…”

“…Anal. calcd for C 12 H 24 N 2 S: C 63.10,H 10.58,N 12.27,S 14.05,found: C 63.46,H 10.79,N 12.04,9aR)-(octahydro-2H-quinolizin-1-yl)methylthio]ethylamino} acridine (42) A mixture of 6,9-dichloro-2-methoxyacridine (0.49 g, 1.75 mmol), the above amine (0.40 g, 1.75 mmol) and phenol (1.10 g) was heated for 5 h at 110 C. After cooling the mixture was treated with 2N NaOH till strong alkalinity and extracted with ether. The organic phase was washed with 2N NaOH, then with H 2 O and, finally, extracted with 5% acetic acid.…”

“…48 ClN 3 OS: C 66.43,H 6.86,N 8.94,S 6.82,found: C 66.15,H 6.88,N 8.89,S 6.53. 8.1.10. 6-Chloro-2-methoxy-9-{N-[3-(1S,9aR)-(octahydro-2H-quinolizin-1-yl)methylthio]propyl amino}acridine (43) According to the procedure already described [42], the title compound was obtained as a yellow solid with m.p. ¼ 78e80 C (yield 61.8%), instead of an oil (yield 22% H 7.08, N 8.68, S 6.62, found: C 66.74, H 6.99, N 8.42, S 6.33.…”

Synthesis of acridine cyclic imide hybrid molecules and their evaluation for anticancer activity

“…Various research groups all over the world are involved in search of lead molecules (Su et al, 2006;Bacherikov et al, 2005;Wang et al, 2007;Desbois et al, 2008;Sedlacek et al, 2012;Janovec et al, 2011;Lang et al, 2013), which can be developed as anticancer drugs with fewer side effects. Acridine derivatives exhibiting antimalarial (Tomer et al, 2010;Guetzoyan et al, 2009), antimicrobial (Prabakaran et al, 2011), antibacterial (Daghigh et al, 2014) antiprion (Thi et al, 2008;Villa et al, 2011), anti-herpes (Goodell et al, 2006), antiviral , anticancer (Teitelbaum et al, 2012;Gardette et al, 2014;El-Deiry, 2008) activities are well documented in literature. Acridine derivatives also act as inhibitors of cholinesterase (Ip et al, 2008;Szymanski et al, 2012), telomerase (Hummersone et al, 2012) and human carbonic anhydrase isoenzymes (Yesildag et al, 2014).…”