Hetero-bifunctional molecules as possible therapeutics for the treatment of Alzheimer’s disease.

Alzheimer’s disease (AD) is the most common form of dementia, currently affecting more than 50 million people worldwide. In recent years attention towards this disease has risen in search for discovery and development of a drug that can stop it. Indeed, therapies for AD provide only temporary symptomatic relief. The cause for the high attrition rate for AD drug discovery has been attributed to several factors, including the fact that the AD pathogenesis is not yet fully understood. Nevertheless, what is increasingly recognized is that AD is a multifactorial syndrome, characterized by many conditions which may lead to neuronal death. Given this, it is widely accepted that a molecule able to modulate more than one target would bring benefit to the therapy of AD. In the first chapter of this thesis, there are reported two projects regarding the design and synthesis of new series of GSK-3/HDAC dual inhibitors, two of the main enzymes involved in AD. Two different series of compounds were synthesized and evaluated for their inhibitory activity towards the target enzymes. The best compounds of the series were selected for further biologic investigation to evaluate their properties. The second project focused on the design of non ATP-competitive GSK-3 inhibitors combined with HDAC inhibition properties. Also in this case, the best compounds of the series were selected for biologic investigation to further evaluate their properties. In chapter 2, the design and synthesis of a GSK-3-directed Proteolysis Targeting Chimeras (PROTAC), a new technology in drug discovery that act through degradation rather than inhibition, is reported. The design and synthesis of a small series of GSK-3-directed PROTACs was achieved. In vitro assays were performed to evaluate the GSK-3-degradation ability, the effective involvement of E3 ubiquitine ligase in the process and their neuroprotective abilities.

Valorization and recycling of waste biomass and bioplastics into molecules, polymers and catalysts

The enormous amount of goods that world societies consume every day, derives from an immense consumption of energy and raw materials, and leads to an unthinkable amount of wastes. The abuse of fossil-based resources and the mismanaged waste is leading to big environmental pollution and climate change, with consequences on all living beings. To solve this issue and start living in equilibrium with nature, modern societies must stop using fossil fuels massively in favor to clean renewable energies, recycling, and biomass and waste utilization for materials and chemical production. Moreover, bioplastic recycling must be prioritized over their biodegrading and composting. This work is dedicated to the study of new synthetic strategies that fall into these fields.

Electrochemistry of polycyclic aromatic molecules for advanced carbon nanostructures: luminescence and transistor applications

Polycyclic aromatic hydrocarbons (PAHs) are a large class of π-conjugated organic molecules with fused aromatic rings, which can be considered as fragments of 2D-graphene and have been extensively studied for their unique optical and electronic properties. The aim of this study is to understand the complex electrochemical behaviour of planar, curved, and heteroatom doped polycyclic aromatic molecules, particularly focusing on the oxidative coupling of their radical cations and the electrochemically induced cyclodehydrogenation reactions. In the first part of this thesis, the class of PAHs and aromatic nanostructures are introduced, and the reactivity of electrogenerated species is discussed, focusing on the electrochemical approach for the synthesis of extended π-conjugated structures. Subsequently, the electrochemical properties and reactivity of electrogenerated radical ions of planar and curved polyaromatics are correlated to their structures. In the third chapter, electrochemical cyclodehydrogenation of hexaphenylbenzene is used to prepare self-assembled hexabenzocoronene, directly deposited on an interdigitated electrode, which was characterised as organic electrochemical transistor. In the fourth chapter, the electrochemical behaviour of a family of azapyrene derivatives has been carefully investigated together with the electrogenerated chemiluminescence (ECL), both by ion-annihilation and co-reactant methods. Two structural azapyrene isomers with different nitrogen positions are thoroughly discussed in terms of redox and ECL properties. Interestingly, the ECL of only one of them showed a double emission with excimer formation. A detailed mechanism is discussed for the ECL by co-reactant benzoyl peroxide, to rationalise the different ECL behaviours of the two isomers on the basis of their topologically modulated electronic properties. In conclusion, the different electrochemical behaviours of PAHs were shown, focussing on the chemical reactivity of the electrogenerated species and taking advantage of it for important processes spanning from unconventional synthesis methods for carbon nanostructures to the exploitation of self-assembled nanostructured systems in organic electronics, to novel organic emitters in ECL.