Potent inhibition of scrapie prion replication in cultured cells by bis-acridines.
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.
May
Barnaby C H
BC
Department of Cellular and Molecular Pharmacology, Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA.
Fafarman
Aaron T
AT
Hong
Septima B
SB
Rogers
Michael
M
Deady
Leslie W
LW
Prusiner
Stanley B
SB
Cohen
Fred E
FE
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D018620:PrPSc Proteins / Q000096:biosynthesis* / Q000187:drug effects*; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology
D000166:Acridines; D018620:PrPSc Proteins; D011796:Quinacrine