NR ANRX
AU May,B.C.H.; Fafarman,A.T.; Hong,S.B.; Rogers,M.; Deady,L.W.; Prusiner,S.B.; Cohen,F.E.
TI Potent inhibition of scrapie prion replication in cultured cells by bis-acridines
QU Proceedings of the National Academy of Sciences of the United States of America 2003 Mar 18; 100(6): 3416-21
PT journal article
AB Prion diseases are characterized by an accumulation of PrPsc, a misfolded isoform of the normal cellular prion protein, PrPc. We previously reported the bioactivity of acridine-based compounds against PrPsc 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 PrPsc 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-y lamino)-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-methox y-acridin-9-ylamino)-propyl]-carbamoyl]-ethyl)-carbamic acid tert-butyl ester, showed half-maximal inhibition of PrPsc 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.
AD Department of Cellular and Molecular Pharmacology, Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA
SP englisch
PO USA
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