ABSTRACT
(E)-6-Methyl-4'-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aß and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aß self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).
Subject(s)
Antioxidants/therapeutic use , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Prion Diseases/drug therapy , Thioctic Acid/therapeutic use , Animals , Antioxidants/chemistry , Antioxidants/pharmacology , Cell Line , Cell Survival/drug effects , Enzyme Inhibitors/pharmacology , PrPSc Proteins/metabolism , Prion Diseases/metabolism , Prion Diseases/pathology , Scrapie/metabolism , Scrapie/pathology , Structure-Activity Relationship , Thioctic Acid/analogs & derivatives , Thioctic Acid/chemical synthesis , Thioctic Acid/pharmacologyABSTRACT
A library of 11 entries, featuring a 2,5-diamino-1,4-benzoquinones nucleus as spacer connecting two aromatic prion recognition motifs, was designed and evaluated against prion infection. Notably, 6-chloro-1,2,3,4-tetrahydroacridine 10 showed an EC(50) of 0.17 µM, which was lower than that displayed by reference compound BiCappa. More importantly, 10 possessed the capability to contrast prion fibril formation and oxidative stress, together with a low cytotoxicity. This study further corroborates the bivalent strategy as a viable approach to the rational design of anti-prion chemical probes.
Subject(s)
Acridines/chemical synthesis , Amines/chemical synthesis , Benzoquinones/chemical synthesis , PrPSc Proteins/antagonists & inhibitors , Acridines/chemistry , Acridines/pharmacology , Amines/chemistry , Amines/pharmacology , Animals , Benzoquinones/chemistry , Benzoquinones/pharmacology , Cell Line , Cell Survival/drug effects , Mice , Oxidative Stress/drug effects , Structure-Activity RelationshipABSTRACT
A small library combining two different benzoquinone cores with seven (L) amino acid methyl esters (alanine, Nomega-nitro-arginine, Nepsilon-BOC-lysine, isoleucine, methionine, phenylalanine and tryptophan) was prepared and tested for prion replication inhibition in ScGT1 cells. The most potent hit, 6a, displayed an EC(50) value of 0.87 microM, which is very close to that of quinacrine (0.4 microM).
Subject(s)
Benzoquinones/chemical synthesis , Molecular Probes , Prions/chemistry , Proteins/chemistry , Benzoquinones/chemistry , Cell Line , Protein BindingABSTRACT
Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 microM, ERbeta at 8.8 microM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 microM. PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 microM, antagonizing at 101/80 microM. AEA antagonized ERalpha/ERbeta at 150/140 microM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.