Design and synthesis of (pro)electrophilic compounds for investigating the multifactorial nature of neurodegenerative diseases: focus on inflammation-driven events

Basagni, Filippo (2021) Design and synthesis of (pro)electrophilic compounds for investigating the multifactorial nature of neurodegenerative diseases: focus on inflammation-driven events, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biotecnologiche, biocomputazionali, farmaceutiche e farmacologiche, 33 Ciclo. DOI 10.48676/unibo/amsdottorato/9676.
Documenti full-text disponibili:
[img] Documento PDF (English) - Richiede un lettore di PDF come Xpdf o Adobe Acrobat Reader
Disponibile con Licenza: Salvo eventuali più ampie autorizzazioni dell'autore, la tesi può essere liberamente consultata e può essere effettuato il salvataggio e la stampa di una copia per fini strettamente personali di studio, di ricerca e di insegnamento, con espresso divieto di qualunque utilizzo direttamente o indirettamente commerciale. Ogni altro diritto sul materiale è riservato.
Download (8MB)

Abstract

Neuroinflammation constitutes a major player in the etiopathology of neurodegenerative diseases (NDDs), by orchestrating several neurotoxic pathways which in concert lead to neurodegeneration. A positive feedback loop occurs between inflammation, microglia activation and misfolding processes that, alongside excitotoxicity and oxidative events, represent crucial features of this intricate scenario. The multi-layered nature of NDDs requires a deepen investigation on how these vicious cycles work. This could further help in the search for effective treatments. Electrophiles are critically involved in the modulation of a variety of neuroprotective responses. Thus, we envisioned their peculiar ability to switch on/off biological activities as a powerful tool for investigating the neurotoxic scenario driven by inflammation in NDDs. In particular, in this thesis project, we wanted to dissect at a molecular level the functional role of (pro)electrophilic moieties of previously synthesized thioesters of variously substituted trans-cinnamic acids, to identify crucial features which could interfere with amyloid aggregation as well as modulate Nrf2 and/or NF-κB activation. To this aim, we first synthesized new compounds to identify bioactive cores which could specifically modulate the intended target. Then, we systematically modified their structure to reach additional pathogenic pathways which could in tandem contribute to the inflammatory process. In particular, following the investigation of the mechanistic underpinnings involving the catechol feature in amyloid binding through the synthesis of new dihydroxyl derivatives, we incorporated the identified antiaggregating nucleus into constrained frames which could contrast neuroinflammation also through the modulation of CB2Rs. In parallel, Nrf2 and/or NF-κB antinflammatory structural requirements were combined with the neuroprotective cores of pioglitazone, an antidiabetic drug endowed with MAO-B inhibitory properties, and memantine, which notably contrasts excitotoxicity. By acting as Swiss army knives, the new set of molecules emerge as promising tools to deepen our insights into the complex scenario regulating NDDs.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Basagni, Filippo
Supervisore
Dottorato di ricerca
Ciclo
33
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
Electrophiles Neuroinflammation Neurodegenerative diseases Proelectrophiles Polyphenols Natural compounds Cytokines Alzheimer’s disease Oxidative stress Beta amyloid Nrf2 NF-kB Drug discovery Coumarine Cannabinoid receptor Microglia Monoamino oxidase Memantine Pioglitazone NMDA receptor Cinnamic acid
URN:NBN
DOI
10.48676/unibo/amsdottorato/9676
Data di discussione
21 Maggio 2021
URI

Altri metadati

Statistica sui download

Gestione del documento: Visualizza la tesi

^