TY - JOUR
T1 - Versatility of the Curcumin Scaffold
T2 - Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors
AU - Di Martino, Rita Maria Concetta
AU - De Simone, Angela
AU - Andrisano, Vincenza
AU - Bisignano, Paola
AU - Bisi, Alessandra
AU - Gobbi, Silvia
AU - Rampa, Angela
AU - Fato, Romana
AU - Bergamini, Christian
AU - Perez, Daniel I.
AU - Martinez, Ana
AU - Bottegoni, Giovanni
AU - Cavalli, Andrea
AU - Belluti, Federica
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2016/1/28
Y1 - 2016/1/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84964297885&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b00894
DO - 10.1021/acs.jmedchem.5b00894
M3 - Article
SN - 0022-2623
VL - 59
SP - 531
EP - 544
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -