The aim of the work was to explore the practical applicability of molecular dynamics at different length and time scales. From nanoparticles system over colloids and polymers to biological systems like membranes and finally living cells, a broad range of materials was considered from a theoretical standpoint. In this dissertation five chemistry-related problem are addressed by means of theoretical and computational methods. The main results can be outlined as follows. (1) A systematic study of the effect of the concentration, chain length, and charge of surfactants on fullerene aggregation is presented. The long-discussed problem of the location of C60 in micelles was addressed and fullerenes were found in the hydrophobic region of the micelles. (2) The interactions between graphene sheet of increasing size and phospholipid membrane are quantitatively investigated. (3) A model was proposed to study structure, stability, and dynamics of MoS2, a material well-known for its tribological properties. The telescopic movement of nested nanotubes and the sliding of MoS2 layers is simulated. (4) A mathematical model to gain understaning of the coupled diffusion-swelling process in poly(lactic-co-glycolic acid), PLGA, was proposed. (5) A soft matter cell model is developed to explore the interaction of living cell with artificial surfaces. The effect of the surface properties on the adhesion dynamics of cells are discussed.

The main aim of this work was the synthesis and applications of functionalized-silica-supported gold nanoparticles. The silica-anchored functionalities employed, e.g. amine, alkynyl carbamate and sulfide moieties, possess a notable affinity with gold, so that they could be able to capture the gold precursor, to spontaneously reduce it (possibly at room temperature), and to stabilize the resulting gold nanoparticles. These new materials, potentially suitable for heterogeneous catalysis applications, could represent a breakthrough among the “green” synthesis of supported gold nanoparticles, since they would circumvent the addition of extra reducing agent and stabilizers, also allowing concomitant absorption of the active catalyst particles on the support immediately after spontaneous formation of gold nanoparticles. In chapter 4 of this thesis is also presented the work developed during a seven-months Marco Polo fellowship stay at the University of Lille (France), regarding nanoparticles nucleation and growth inside a microfluidic system and the study of the corresponding mechanism by in situ XANES spectroscopy. Finally, studies regarding the reparation and reactivity of gold decorated nanodiamonds are also described. Various methods of characterization have been used, such as ultraviolet-visible spectroscopy (UV-Vis), Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), X-ray Fluorescence (XRF), Field Emission Gun Scanning Electron Microscopy (SEM-FEG), X-ray Photoionization (XPS), X ray Absorption Spectroscopy (XAS).

This PhD research project deals with the synthesis and characterization of supramolecular photoresponsive systems based on the azobenzene unit. 1)Azobenzene-cyclodextrin inclusion complexes: the aim of this study was to obtain relatively simple, water-soluble derivatives, whose self-assembly could be reversibly controlled by light. On the basis of previous results, this opens the possibility of directly converting light into mechanical energy via osmosis. Several new azobenzene functionalized cyclodextrins have been synthesized, fully characterized and studied The inclusion complexes thus formed and their light-driven disassembly were studied by means of several complementary techniques including NMR, UV, CD, ICT, mass spectroscopy. The most suitable systems were used in experiments, still in progress, of light-to-mechanical energy conversion. 2)Azobenzene-guanosine hybrids: several novel azobenzene-guanosine hybrids were synthesized for the purpose of investigating the effect of cis-trans photoisomerization on guanosine self-assembly. Lipophilic guanosines in organic solvents can form either ribbon-like supramolecular polymers or, in the presence of alkali metal ions, G-quartet based supramolecular complexes. These complexes were fully characterized for newly synthesized azobenzene-guanosine hybrids. In the absence of ions, the ribbon-like supramolecular polymer gives rise to a gel-like system, which turned out to be a lyotropic liquid crystalline phase. Photoisomerization to cis form induces the transition to an isotropic solution, in a reversible fashion. In addition, the G-quartet structure obtained in the presence of alkali metal ions can be disassembled by light. 3) Oligoazobenzenes’s project. While several examples of electron-rich conjugated polymers are known and find application e.g. as electron donors in “plastic” photovoltaics, no examples are reported on the use of electron-poor conjugated polymers as acceptor counterpart. In particular, no polyazobenzenes having the (-C6H4-N=N-) repeat unit have ever been reported. Although no polymeric has been obtained yet, we succeeded in synthesizing several homologues up to a tetramer. The compounds were subjected to photophysical, photochemical and electrochemical characterization.

In this thesis the results of a Computational Organic Chemistry Ph.D. work course ranging from organometallic to metal-free and enzymatic catalysis is discussed. Various energetic and mechanistic aspects of organic reactions in catalysis are the key-issues which are addressed. A multidisciplinary approach allowed the development of several research projects in collaboration with experimental groups and combined experimental-theoretical works were carried out. Notes and comments concerning the theoretical models used and the experimental work carried out by the research groups who cooperated with us, are reported. The thesis comprises four main sections. The first section provides basic information on the computational methods used in the present work. In the subsequent sections (Part II, Part III and Part IV) we focus on different aspects of organic catalysis. In Part II the results of computational studies on the mechanism of various metal-catalyzed reactions are presented. In particular we describe organic reactions catalyzed by Gold(I) complexes. We consider some synthetically important processes in organic chemistry. The purpose of these studies was to discover some general rules to rationalize the role of gold complexes in different classes of organic reactions. Furthermore, at the end of this section we describe a mechanistic investigation of an example of organo-catalysis, thus not involving metal complexes. In Part III we focus on an emerging and promising area of "metal-free" catalysis, based on carbon nanostructures such as graphite, graphene, graphene oxide, fullerenes and carbon nanotubes (CNTs). This “metal-free” catalysis is usually denoted as Carbocatalysis. The energy contributions that may influence the course of a reaction inside a CNT, have been elucidated by means of computational methods. In Part IV the computational approach is used to elucidate the mechanism of an enzymatic reaction. We describe the results obtained in the study of tyrosine O-sulfonation catalyzed by human Tyrosylprotein Sulfotransferases-2.

The work described in this thesis was performed in order to develop advanced analytical methods suitable to select and characterize GS- 3β inhibitors in vitro. GSK-3β is recognized as a key target for the development of new therapeutic agents for Alzheimer disease (AD). We validated an UHPLC-UV-Vis diode arrays detector (DAD) method for the very fast identification (resolution in less than 2 min) and determination of ADP and ATP in enzyme-based assay containing GSM-S syntetic peptide, ATP and GSK-3β. By using this method, selected inhibition hits will be characterized by defining their competitive mode of action with the substrate rather than with the ATP cofactor, in view of the discovery of compounds endowed of an increased GSK-3β selectivity over other protein-kinases. Next we hypothesized that GSK-3β could be directly involved in the regulation of histone acetylation through HDAC protein. Our hypothesis accounts that inhibition of GSK-3β, which leads to reduced HDAC activity, could restores the acetylation level in histones, protecting against neurodegeneration as both aging and AD pathology are associated with loss of histone acetylation (H4/H3) at N-terminus. Therefore, quantification of histone modifications on individual lysine residues is of crucial importance to understand their role in cell biology. We developed a targeted liquid chromatography mass spectrometry (LC-MS) method for the site-specific quantification of lysine acetylation in the N-terminal region of histone H4 from murine macrophage-like cell line RAW 264.7, with the perspective to apply the method on neuronal cells upon administration of GSK-3β inhibitors. The analytical strategy we developed shows that careful optimization of chemical derivatization steps at the protein and at the peptide level, combined with a more extensive digestion using chymotrypsin and trypsin, allows to differentiate between acetylation levels of each lysine residues.

The development of lithium-ion batteries (LIBs) with specific energy >200 Wh/kg plays a key role to boost the progress of sustainable transport and to promote the large-scale diffusion of electric vehicles with long electric-driving-range. The battery energy density can be increased by using high-voltage and/or high-capacity cathode materials. LiNi0.4Mn1.6O4 and LiNi0.5Mn1.5O4 are among the most promising cathode materials for the high theoretical specific capacity and high nominal operating voltage. However, the major concern is about their reactivity towards conventional electrolytes that decompose at high potentials leading to thick surface layers on the cathode resulting in capacity loss. This PhD work deals with the development of high energy and power LIBs featuring LiNi0.4Mn1.6O4 and LiNi0.5Mn1.5O4 cathodes, mainly for hybrid electric vehicle (HEV) applications. Starting from the challenging study of cell components such as electrolyte, separator, electrode conductive additive and binder, full cells with graphite anodes were assembled and tested according to the US Dept. of Energy (DOE) protocols for the use in power-assist and plug-in HEV applications. The use of a carbonate-based electrolyte with a fluorinated non-conventional lithium salt and of the reinforced polyvinylidene fluoride (PVdF) macroporous membrane as separator significantly improve the electrochemical performance of graphite//LiNi0.4Mn1.6O4 cells with respect to those with the conventional electrolyte and commercial separator. The study of different conductive additives on the cycling performance of LiNi0.5Mn1.5O4 electrodes demonstrated that reduced graphene oxides improve the electrode/electrolyte interface by acting as a protective barrier that hinders the formation of a thick passivation layer on the cathode surface. The study of water-soluble binder proved that carboxymethyl cellulose remarkably improve the cycling performance of LiNi0.5Mn1.5O4 electrodes compared to those with conventional PVdF binder. Characterization tests according DOE protocols on graphite//LiNi0.4Mn1.6O4 and graphite//LiNi0.5Mn1.5O4 confirmed that these cells meet the DOE targets of energy and power for power-assist and plug-in HEVs.

The main topics explored in this thesis regard the synthesis of some new polythiophenes for the preparation of efficient and stable polymeric solar cell with the bulk heterojunction architecture and the study of the mechanism involved in the radical emulsion polymerization of VDF/HFP to obtain copolymers with an optimized thermal and mechanical behavior.

Polypharmacology-based strategies are gaining ever-increasing attention as useful approaches to develop disease-modifying drug candidates for effective Alzheimer’s disease (AD) treatment. In this scenario, multitarget-directed ligands could increase efficiency by simultaneous modulation of several targets involved in AD pathogenesis. In drug discovery, natural products (NPs) represent an excellent source of evolutionary-chosen “privileged structures”. In this thesis, the polyphenol curcumin, found in Curcuma longa L, encompassing the essential structural elements for the concurrent inhibition of two validated AD targets, BACE-1 and GSK-3β, was rationally identified as lead compound. Aimed at developing well-balanced dual BACE-1/GSK-3β modulators with good BBB permeability, different series of curcumin-based derivatives were designed and synthetized by introducing suitable chemical modifications on the side aryl ring(s) and in the 4-position of the main scaffold. Furthermore, considering the pivotal role of the intramolecular H-bond network of curcumin’s central fragment in establishing appropriate interactions with target binding sites, several complexation and bioisosteric cyclization strategies were performed. Thanks to its strong Michael acceptor reactivity toward critical cysteine residues, curcumin exerts neuroprotection by additional activation of the Keap1-Nrf2-ARE signaling pathway. Thus, aimed at affecting the electrophilicity of its α,β-unsaturated carbonyl fragment, allowing a fine-tuning of its reactivity, diverse electrophilic functions were inserted in different positions of the curcumin scaffold. Furthermore, considering the neuroprotective and antioxidant potentials of simple coumarins, several curcumin-coumarin hybrids were also prepared. Recently, the inhibition of additional AD-correlated protein kinases (PKs), such as CK1 and LRRK2, could offer promises to achieve a successful treatment and indole was envisaged as useful scaffold for both PKs’ inhibition. Thus, a small library of indole-based derivatives was designed and synthetized as valuable BBB permeable pharmacological tools. Finally, chitosan (CS), a natural, nontoxic, biocompatible and biodegradable polysaccharide, was selected to develop CS-based bioconjugates for nanoparticles’ preparation as innovative drug delivery and targeting systems.

Thiophene based oligomers and polymers are of great current interest from a scientific and technological point of view for their numerous properties: they are electroactive, fluorescent, chemically stable and allow a great diversity in molecular structures and a fine tuning of functional characteristics. They display ‘plasticity’ in adapting their geometry to the environment in the solid state and in creating supramolecular architectures by self-organization. Moreover, they have the capability to finely interact with biologically relevant molecules such as intracellular proteins. All these properties allow a large number of different applications in fields such as organic electronics and bioimaging which prompted the development of highly efficient and ‘user friendly’ synthetic approaches for their preparation. We have synthesized unprecedented classes of functional thiophene based materials by employing enabling technologies such as microwave and ultrasound irradiation in order to obtain oligo and polythiophenes in very pure form and high yields. Preparing oligo- and polythiophenes in very pure form by means of rapid and environmentally friendly procedures is crucial for application of these compounds in materials chemistry as semiconductor and fluorescent compounds for electronic and optoelectronic devices as well as for application in cell imaging and monitoring of intracellular processes.

The activity carried out during my PhD was principally addressed to the development and characterization of new detection systems based on chemical luminescence (CL) for the implementation into smartphone based-biosensors for point of care (POC) and point of need applications. The aim of this research has been to determine the feasibility of combining smartphone detection capabilities with CL dependent assay results. In particular, my work has concerned the development of two smartphone-based assays to image and quantify chemiluminescence coupled biospecific enzymatic reactions to detect total cholesterol in serum and lactate in oral fluid and sweat. The devices were produced using a low-cost 3D printing technology and include a disposable analytical minicartridge, a mini dark box to avoid interference from ambient light measurement, and a holder to connect the dark box to a smartphone. The performances of these systems were compared with those obtained with a reference laboratory instrumentation (thermoelectrically cooled MZ-2PRO CCD camera). Finally, it was developed an alternative non-invasive smartphone-based assay to quantify lactate in oral fluid using a reagentless bioactive paper-based solid-phase biosensor integrated in smartphone-based device, employing light reflectance to measure an end-point enzymatic chemical reaction. The quantitative information is obtained from the change of color, due to variability of amount, intensity and brightness of light reflected from surface where assay has occurred. The proposed approaches based on the use of smartphone as detector paves the way for a new generation of analytical devices in the clinical diagnostic field. Moreover, the connectivity and data processing offered by smartphones can be exploited to perform analysis directly at home with simple procedures. The extreme simplicity of the device widens it applicability and makes it suitable for the detection of many analytes of clinical interest, for instance H2O2 producing all kind of oxidases.