Mitochondrial diseases can result from an alteration of the mitochondrial respiratory chain function, particularly oxidative phosphorylation (OXPHOS), leading to a range of disorders, including Parkinson's disease (PD). Currently, there are several drugs on the market that treat symptoms severity but do not contribute to slow down PD progression. It has been recently shown that one of the triggers for the pathogenesis and progression of PD could be related to dysfunctions of the Complex I of the electron transport chain (ETC) in mitochondria. This project is part of a larger study coordinated by the research group of Prof. Szabò of the Department of Biology at the University of Padova and focuses on the employment of a particular class of organic compounds, named redox cyclers, such as 5-hydroxy-1,4-naphthalenedione (juglone), to replace the redox functions of impaired Complex I by transferring electrons from NADH to ubiquinone, thus restoring proper mitochondrial functions. However, some drawbacks emerge in using juglone redox cycler as a therapeutic agent. Indeed, it is crucial that juglone is used in sub-micromolar (sub-µM) doses, as higher amounts result in significant production of reactive oxygen species (ROS), such as superoxide radicals, leading to cell toxicity. In addition, juglone is rapidly metabolized, and excreted from the body due to the low molecular weight, the presence of polarizable functional groups, and hydrogen bond acceptor and donor groups. Moreover, such molecular features make its pharmacology promiscuous, leading to undesirable off-target effects. This thesis focuses on improving the ADMET (Absorption, Distribution, Metabolism, and Excretion–Toxicity) properties of juglone. Specifically, molecular complexity was increased to achieve a dual benefit: prolonging the compound’s half-life and reducing potential undesirable pro-oxidant effects. Five new juglone analogues have been synthesized and characterized using synthetic procedures developed and optimized in the laboratories of Prof. Mattarei of the Department of Pharmaceutical and Pharmacological Sciences at the University of Padova. Finally, in collaboration with the research group of Prof. Durante of the Department of Chemical Sciences at the University of Padova, cyclic voltammetry was used to assess whether the required redox cycler properties were retained in the newly synthesized analogues. Future developments in this project involve the use of these compounds in in vitro and in vivo models to evaluate their toxicity, pharmacokinetic parameters, and metabolism. The compounds will be finally tested for their efficacy in counteracting respiratory chain dysfunctions, in particular in PD murine models.
Le malattie mitocondriali possono derivare da un'alterazione della funzione della catena respiratoria mitocondriale, in particolare della fosforilazione ossidativa (OXPHOS), portando a una serie di disturbi, tra cui la malattia di Parkinson (PD). Attualmente, esistono diversi farmaci sul mercato che trattano i sintomi, ma non contribuiscono a rallentare la progressione del PD. È stato recentemente dimostrato che uno dei fattori scatenanti della patogenesi e della progressione del PD potrebbe essere correlato a disfunzioni del Complesso I della catena di trasporto degli elettroni (ETC) nei mitocondri. Questo progetto, parte di uno studio più ampio coordinato dal gruppo di ricerca della Prof. Szabò del Dipartimento di Biologia dell'Università di Padova, si concentra sull'impiego di una particolare classe di composti organici, chiamati redox cyclers, come il 5-idrossi-1,4-naftalenedione (juglone), per sostituire le funzioni redox del Complesso I danneggiato trasferendo elettroni dal NADH all'ubichinone, ripristinando così le normali funzioni mitocondriali. Tuttavia, emergono alcuni svantaggi nell'uso del juglone come agente terapeutico. È infatti cruciale che il juglone venga utilizzato in dosi sub-micromolari (sub-µM), poiché quantità superiori comportano una significativa produzione di specie reattive dell'ossigeno (ROS), come i radicali superossido, che portano a tossicità cellulare. Inoltre, il juglone è rapidamente metabolizzato ed escreto dall'organismo troppo velocemente a causa del suo basso peso molecolare, della presenza di gruppi funzionali polarizzabili e di gruppi accettori e donatori di legami idrogeno. Queste caratteristiche molecolari, inoltre, rendono la sua farmacologia promiscua, portando a indesiderati effetti off-target. Questa tesi si concentra sul miglioramento delle proprietà ADMET (Assorbimento, Distribuzione, Metabolismo ed Escrezione–Tossicità) del juglone. In particolare, la complessità molecolare è stata aumentata per ottenere un duplice beneficio: prolungare l'emivita del composto e ridurre i potenziali effetti pro-ossidanti indesiderati. Sono stati sintetizzati e caratterizzati cinque nuovi analoghi del juglone utilizzando procedure sintetiche sviluppate e ottimizzate nei laboratori del Prof. Mattarei del Dipartimento di Scienze del Farmaco dell'Università di Padova. Infine, in collaborazione con il gruppo di ricerca del Prof. Durante del Dipartimento di Scienze Chimiche dell'Università di Padova, è stata utilizzata la voltammetria ciclica per valutare se le desiderate proprietà di redox cycler fossero mantenute nei nuovi analoghi sintetizzati. I futuri sviluppi di questo progetto prevedono l'uso di questi composti in modelli in vitro e in vivo per valutarne la tossicità, i parametri farmacocinetici e il metabolismo. I composti verranno infine testati per la loro efficacia nel contrastare le disfunzioni della catena respiratoria, in particolare nei modelli murini di PD.
Design, synthesis and electrochemical characterization of 5-hydroxy-1,4-naphthalenedione-derived redox cyclers for the treatment of mitochondrial diseases
DONADELLO, EDOARDO
2023/2024
Abstract
Mitochondrial diseases can result from an alteration of the mitochondrial respiratory chain function, particularly oxidative phosphorylation (OXPHOS), leading to a range of disorders, including Parkinson's disease (PD). Currently, there are several drugs on the market that treat symptoms severity but do not contribute to slow down PD progression. It has been recently shown that one of the triggers for the pathogenesis and progression of PD could be related to dysfunctions of the Complex I of the electron transport chain (ETC) in mitochondria. This project is part of a larger study coordinated by the research group of Prof. Szabò of the Department of Biology at the University of Padova and focuses on the employment of a particular class of organic compounds, named redox cyclers, such as 5-hydroxy-1,4-naphthalenedione (juglone), to replace the redox functions of impaired Complex I by transferring electrons from NADH to ubiquinone, thus restoring proper mitochondrial functions. However, some drawbacks emerge in using juglone redox cycler as a therapeutic agent. Indeed, it is crucial that juglone is used in sub-micromolar (sub-µM) doses, as higher amounts result in significant production of reactive oxygen species (ROS), such as superoxide radicals, leading to cell toxicity. In addition, juglone is rapidly metabolized, and excreted from the body due to the low molecular weight, the presence of polarizable functional groups, and hydrogen bond acceptor and donor groups. Moreover, such molecular features make its pharmacology promiscuous, leading to undesirable off-target effects. This thesis focuses on improving the ADMET (Absorption, Distribution, Metabolism, and Excretion–Toxicity) properties of juglone. Specifically, molecular complexity was increased to achieve a dual benefit: prolonging the compound’s half-life and reducing potential undesirable pro-oxidant effects. Five new juglone analogues have been synthesized and characterized using synthetic procedures developed and optimized in the laboratories of Prof. Mattarei of the Department of Pharmaceutical and Pharmacological Sciences at the University of Padova. Finally, in collaboration with the research group of Prof. Durante of the Department of Chemical Sciences at the University of Padova, cyclic voltammetry was used to assess whether the required redox cycler properties were retained in the newly synthesized analogues. Future developments in this project involve the use of these compounds in in vitro and in vivo models to evaluate their toxicity, pharmacokinetic parameters, and metabolism. The compounds will be finally tested for their efficacy in counteracting respiratory chain dysfunctions, in particular in PD murine models.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/80297