Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

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• 作者：Elisabet Viayna ; Irene Sola ; Manuela Bartolini ; Angela De Simone ; Cheril Tapia-Rojas ; Felipe G. Serrano ; Raimon Sabat茅 ; Jordi Ju谩rez-Jim茅nez ; Bel茅n P茅rez ; F. Javier Luque ; Vincenza Andrisano ; M. Vict貌ria Clos ; Nibaldo C. Inestrosa ; Diego Mu帽oz-Torrero
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2549-2567
• 全文大小：730K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

We have synthesized a family of rhein鈥揾uprine hybrids to hit several key targets for Alzheimer鈥檚 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 A尾42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (鈭?-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the A尾-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 (鈭?-7e have shown a central soluble A尾 lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (鈭?-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.