title: Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents.
abstract: We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Aβ42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona , Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.forename: Cheril
authors.initials: C
authors.lastname: Tapia-Rojas
authors.forename: Felipe G
authors.initials: FG
authors.lastname: Serrano
authors.forename: Raimon
authors.initials: R
authors.lastname: Sabaté
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors; D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013569:Synapses / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000880:Anthraquinones; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C020491:rhein