Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a neuronal and synaptic loss of the cholinergic system and by the accumulation of amyloid β (Aβ) aggregates and hyperphosphorylated tau protein. Since current therapies offer only temporary benefits to patients, new strategies have been formulated. One of the leading approaches is the development of multi-target ligands, which are able to modulate simultaneously different pathogenic pathways. On the pattern of the previously identified multi-target leads, which displayed the ability to inhibit both cholinesterases (ChEs) and Aβ aggregation, the efforts of my PhD work have concerned the design and synthesis of four different series of naphtho- and anthraquinone derivatives connected through a polymethylene chain of variable length to an (hetero)aromatic ring or a basic moiety. The first set is characterized by the presence of hydrophobic features selected for an efficient interaction with a sequence of aromatic amino acids of Aβ, implicated in the aggregation process. For the others set, the scaffold has been decorated exploiting the piperazine or piperidine ring as basic feature in order to improve the inhibition of ChEs. All the compounds have been evaluated in vitro for the inhibitory activities towards Aβ aggregation and both ChEs. The first set was subsequentially evaluated towards other targets such as Tau and MAO. Then, some promising compounds of the second set have been selected for further biological studies that I performed at the University of Bath (UK) to establish their safety profile and their value as neuroprotective agents and γ-secretase inhibitors. The encouraging results gathered show that these derivatives may exert different potential benefit as non-toxic agents against AD. The challenge will be to move from early biological evaluation (enzyme and cellular level) to the next in vivo stage.

Development of quinone-based systems as new ligands for the treatment of Alzheimer’s disease

CAMPORA, MARTA
2021-03-30

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a neuronal and synaptic loss of the cholinergic system and by the accumulation of amyloid β (Aβ) aggregates and hyperphosphorylated tau protein. Since current therapies offer only temporary benefits to patients, new strategies have been formulated. One of the leading approaches is the development of multi-target ligands, which are able to modulate simultaneously different pathogenic pathways. On the pattern of the previously identified multi-target leads, which displayed the ability to inhibit both cholinesterases (ChEs) and Aβ aggregation, the efforts of my PhD work have concerned the design and synthesis of four different series of naphtho- and anthraquinone derivatives connected through a polymethylene chain of variable length to an (hetero)aromatic ring or a basic moiety. The first set is characterized by the presence of hydrophobic features selected for an efficient interaction with a sequence of aromatic amino acids of Aβ, implicated in the aggregation process. For the others set, the scaffold has been decorated exploiting the piperazine or piperidine ring as basic feature in order to improve the inhibition of ChEs. All the compounds have been evaluated in vitro for the inhibitory activities towards Aβ aggregation and both ChEs. The first set was subsequentially evaluated towards other targets such as Tau and MAO. Then, some promising compounds of the second set have been selected for further biological studies that I performed at the University of Bath (UK) to establish their safety profile and their value as neuroprotective agents and γ-secretase inhibitors. The encouraging results gathered show that these derivatives may exert different potential benefit as non-toxic agents against AD. The challenge will be to move from early biological evaluation (enzyme and cellular level) to the next in vivo stage.
File in questo prodotto:
File Dimensione Formato  
phdunige_3799150.pdf

accesso aperto

Descrizione: Tesi di Dottorato
Tipologia: Tesi di dottorato
Dimensione 5.96 MB
Formato Adobe PDF
5.96 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/11567/1041782
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact