Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

Elisabet Viayna, Irene Sola, Manuela Bartolini, Angela De Simone, Cheril Tapia-Rojas, Felipe G. Serrano, Raimon Sabaté, Jordi Juárez-Jiménez, Belén Pérez, F. Javier Luque, Vincenza Andrisano, M. Victòria Clos, Nibaldo C. Inestrosa, Diego Muñoz-Torrero

Research output: Contribution to journalArticleResearchpeer-review

98 Citations (Scopus)

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. © 2014 American Chemical Society.
Original languageEnglish
Pages (from-to)2549-2567
JournalJournal of Medicinal Chemistry
Volume57
DOIs
Publication statusPublished - 27 Mar 2014

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