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Title: Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents
Author: Viayna, Elisabet
Sola, Irene
Bartolini, Manuela
De Simone, Angela
Tapia-Rojas, Cheril
Serrano, Felipe G.
Sabaté Lagunas, Raimon
Juárez-Jiménez, Jordi
Pérez Fernández, Belén
Luque Garriga, F. Xavier
Andrisano, Vincenza
Clos Guillén, M. Victòria
Inestrosa, Nibaldo C.
Muñoz-Torrero López-Ibarra, Diego
Keywords: Compostos orgànics
Disseny de medicaments
Inhibidors enzimàtics
Malaltia d'Alzheimer
Organic compounds
Drug design
Enzyme inhibitors
Alzheimer's disease
Issue Date: 27-Mar-2014
Publisher: American Chemical Society
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 anti-aggregating 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 i.p. 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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Medicinal Chemistry, 2014, vol. 57, num. 6, p. 2549-2567
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ISSN: 0022-2623
Appears in Collections:Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

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