The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimeŕs disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.

Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors

DI MARTINO, RITA MARIA CONCETTA;DE SIMONE, ANGELA;ANDRISANO, VINCENZA;BISI, ALESSANDRA;GOBBI, SILVIA;RAMPA, ANGELA;FATO, ROMANA;BERGAMINI, CHRISTIAN;BOTTEGONI, GIOVANNI;CAVALLI, ANDREA;BELLUTI, FEDERICA
2016

Abstract

The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimeŕs disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.
2016
Di Martino, Rita Maria Concetta; De Simone, Angela; Andrisano, Vincenza; Bisignano, Paola; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Fato, Romana; Bergamini, Christian; Perez, Daniel I.; Martinez, Ana; Bottegoni, Giovanni; Cavalli, Andrea; Belluti, Federica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/579953
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