Potent inhibition of scrapie prion replication in cultured cells by bis-acridines.

Abstract

Prion diseases are characterized by an accumulation of PrP(Sc), a misfolded isoform of the normal cellular prion protein, PrP(C). We previously reported the bioactivity of acridine-based compounds against PrP(Sc) replication in scrapie-infected neuroblastoma cells and now report the improved potency of bis-acridine compounds. Bis-acridines are characterized by a dimeric motif, comprising two acridine heterocycles tethered by a linker. A library of bis-(6-chloro-2-methoxy-acridin-9-yl) and bis-(7-chloro-2-methoxy-benzo[b][1,5]naphthyridin-10-yl) analogs was synthesized to explore the effect of structurally diverse linkers on PrP(Sc) replication in scrapie-infected neuroblastoma cells. Structure-activity analysis revealed that linker length and structure are important determinants for inhibition of prion replication in cultured scrapied cells. Three bis-acridine analogs, (6-chloro-2-methoxy-acridin-9-yl)-(3-[4-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-piperazin-1-yl]-propyl)-amine, N,N'-bis-(6-chloro-2-methoxy-acridin-9-yl)-1,8-diamino-3,6-dioxaoctane, and (1-[[4-(6-chloro-2-methoxy-acridin-9-ylamino)-butyl]-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-carbamoyl]-ethyl)-carbamic acid tert-butyl ester, showed half-maximal inhibition of PrP(Sc) formation at 40, 25, and 30 nM, respectively, and were not cytotoxic to uninfected neuroblastoma cells at concentrations of 500 nM. Our data suggest that bis-acridine analogs may provide a potent alternative to the acridine-based compound quinacrine, which is currently under clinical evaluation for the treatment of prion disease.

• Authors: Barnaby C H May, Aaron T Fafarman, Septima B Hong, Michael Rogers, Leslie W Deady, Stanley B Prusiner, Fred E Cohen
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 6 Pg. 3416-21 (Mar 18 2003) ISSN: 0027-8424 [Print] United States
• PMID: 12626750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acridines
• PrPSc Proteins
• Quinacrine

Topics

• Acridines (chemistry, pharmacology)
• Animals
• Cell Line
• Drug Evaluation, Preclinical
• Humans
• Mice
• PrPSc Proteins (biosynthesis, drug effects)
• Prion Diseases (drug therapy, metabolism)
• Quinacrine (pharmacology)