Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu2+-induced ROS formation without any direct neurotoxic effect.

Rampa, A., Tarozzi, A., Mancini, F., Pruccoli, L., Di Martino, R.M.C., Gobbi, S., et al. (2016). Naturally inspired molecules as multifunctional agents for Alzheimer's disease treatment. MOLECULES, 21(5), 1-16 [10.3390/molecules21050643].

Naturally inspired molecules as multifunctional agents for Alzheimer's disease treatment

RAMPA, ANGELA;TAROZZI, ANDREA;MANCINI, FRANCESCA;PRUCCOLI, LETIZIA;DI MARTINO, RITA MARIA CONCETTA;GOBBI, SILVIA;BISI, ALESSANDRA;DE SIMONE, ANGELA;PALOMBA, FRANCESCO;ZACCHERONI, NELSI;BELLUTI, FEDERICA
2016

Abstract

Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu2+-induced ROS formation without any direct neurotoxic effect.
2016
Rampa, A., Tarozzi, A., Mancini, F., Pruccoli, L., Di Martino, R.M.C., Gobbi, S., et al. (2016). Naturally inspired molecules as multifunctional agents for Alzheimer's disease treatment. MOLECULES, 21(5), 1-16 [10.3390/molecules21050643].
Rampa, Angela; Tarozzi, Andrea; Mancini, Francesca; Pruccoli, Letizia; Di Martino, Rita Maria Concetta; Gobbi, Silvia; Bisi, Alessandra; De Simone, An...espandi
File in questo prodotto:
File Dimensione Formato  
molecules-21-00643.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione 2.08 MB
Formato Adobe PDF
2.08 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/582723
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 13
social impact