Il cane come modello animale spontaneo di patologie neoplastiche dell'uomo: ene Ataxia-Telangiectasia Mutated (ATM) Nnella predisposizione al cancro ed importanza dei riarrangimanti genici dei geni Ig/TCR per la diagnosi e prognosi delle malattie linfoproliferative

“Naturally occurring cancers in pet dogs and humans share many features, including histological appearance, tumour genetics, molecular targets, biological behaviour and response to conventional therapies. Studying dogs with cancer is likely to provide a valuable perspective that is distinct from that generated by the study of human or rodent cancers alone. The value of this opportunity has been increasingly recognized in the field of cancer research for the identification of cancer-associated genes, the study of environmental risk factors, understanding tumour biology and progression, and, perhaps most importantly, the evaluation and development of novel cancer therapeutics”.(Paoloni and Khanna, 2008) In last years, the author has investigated some molecular features of cancer in dogs. The Thesis is articulated in two main sections. In section 1, the preliminary results of a research project aimed at investigating the role of somatic mutations of Ataxia-Telangiectasia mutated (ATM) gene in predisposing to cancer in boxer dogs, are presented. The canine boxer breed may be considered an unique opportunity to disclose the role of ATM somatic mutation since boxer dogs are known to be dramatically susceptible to cancer and since they may be considered a closed gene pool. Furthermore, dogs share with human the some environment. Overall, the abovementioned features could be considered extremely useful for our purposes. In the section 2, the results of our studies aimed at setting up accurate and sensitive molecular assays for diagnosing and assessing minimal residual disease in lymphoproliferative disorders of dogs, are presented. The results of those molecular assay may be directly translated in the field of Veterinary practice as well as the may be used to improve our objective evaluation of new investigational drugs effectiveness in canine cancer trials.

Development and characterization of non-oxide ceramic composites for mechanical and tribological applications

The main reasons for the attention focused on ceramics as possible structural materials are their wear resistance and the ability to operate with limited oxidation and ablation at temperatures above 2000°C. Hence, this work is devoted to the study of two classes of materials which can satisfy these requirements: silicon carbide -based ceramics (SiC) for wear applications and borides and carbides of transition metals for ultra-high temperatures applications (UHTCs). SiC-based materials: Silicon carbide is a hard ceramic, which finds applications in many industrial sectors, from heat production, to automotive engineering and metals processing. In view of new fields of uses, SiC-based ceramics were produced with addition of 10-30 vol% of MoSi2, in order to obtain electro conductive ceramics. MoSi2, indeed, is an intermetallic compound which possesses high temperature oxidation resistance, high electrical conductivity (21·10-6 Ω·cm), relatively low density (6.31 g/cm3), high melting point (2030°C) and high stiffness (440 GPa). The SiC-based ceramics were hot pressed at 1900°C with addition of Al2O3-Y2O3 or Y2O3-AlN as sintering additives. The microstructure of the composites and of the reference materials, SiC and MoSi2, were studied by means of conventional analytical techniques, such as X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive spectroscopy (SEM-EDS). The composites showed a homogeneous microstructure, with good dispersion of the secondary phases and low residual porosity. The following thermo-mechanical properties of the SiC-based materials were measured: Vickers hardness (HV), Young’s modulus (E), fracture toughness (KIc) and room to high temperature flexural strength (σ). The mechanical properties of the composites were compared to those of two monolithic SiC and MoSi2 materials and resulted in a higher stiffness, fracture toughness and slightly higher flexural resistance. Tribological tests were also performed in two configurations disco-on-pin and slideron cylinder, aiming at studying the wear behaviour of SiC-MoSi2 composites with Al2O3 as counterfacing materials. The tests pointed out that the addition of MoSi2 was detrimental owing to a lower hardness in comparison with the pure SiC matrix. On the contrary, electrical measurements revealed that the addition of 30 vol% of MoSi2, rendered the composite electroconductive, lowering the electrical resistance of three orders of magnitude. Ultra High Temperature Ceramics: Carbides, borides and nitrides of transition metals (Ti, Zr, Hf, Ta, Nb, Mo) possess very high melting points and interesting engineering properties, such as high hardness (20-25 GPa), high stiffness (400-500 GPa), flexural strengths which remain unaltered from room temperature to 1500°C and excellent corrosion resistance in aggressive environment. All these properties place the UHTCs as potential candidates for the development of manoeuvrable hypersonic flight vehicles with sharp leading edges. To this scope Zr- and Hf- carbide and boride materials were produced with addition of 5-20 vol% of MoSi2. This secondary phase enabled the achievement of full dense composites at temperature lower than 2000°C and without the application of pressure. Besides the conventional microstructure analyses XRD and SEM-EDS, transmission electron microscopy (TEM) was employed to explore the microstructure on a small length scale to disclose the effective densification mechanisms. A thorough literature analysis revealed that neither detailed TEM work nor reports on densification mechanisms are available for this class of materials, which however are essential to optimize the sintering aids utilized and the processing parameters applied. Microstructural analyses, along with thermodynamics and crystallographic considerations, led to disclose of the effective role of MoSi2 during sintering of Zrand Hf- carbides and borides. Among the investigated mechanical properties (HV, E, KIc, σ from room temperature to 1500°C), the high temperature flexural strength was improved due to the protective and sealing effect of a silica-based glassy phase, especially for the borides. Nanoindentation tests were also performed on HfC-MoSi2 composites in order to extract hardness and elastic modulus of the single phases. Finally, arc jet tests on HfC- and HfB2-based composites confirmed the excellent oxidation behaviour of these materials under temperature exceeding 2000°C; no cracking or spallation occurred and the modified layer was only 80-90 μm thick.

Molecular analysis of special type breast carcinomas

The project was developed into three parts: the analysis of p63 isoform in breast tumours; the study of intra-tumour eterogeneicity in metaplastic breast carcinoma; the analysis of oncocytic breast carcinoma. p63 is a sequence-specific DNA-binding factor, homologue of the tumour suppressor and transcription factor p53. The human p63 gene is composed of 15 exons and transcription can occur from two distinct promoters: the transactivating isoforms (TAp63) are generated by a promoter upstream of exon 1, while the alternative promoter located in intron 3 leads to the expression of N-terminal truncated isoforms (ΔNp63). It has been demonstrated that anti-p63 antibodies decorate the majority of squamous cell carcinomas of different organs; moreover tumours with myoepithelial differentiation of the breast show nuclear p63 expression. Two new isoforms have been described with the same sequence as TAp63 and ΔNp63 but lacking exon 4: d4TAp63 and ΔNp73L, respectively. Purpose of the study was to investigate the molecular expression of N-terminal p63 isoforms in benign and malignant breast tissues. In the present study 40 specimens from normal breast, benign lesions, DIN/DCIS, and invasive carcinomas were analyzed by immunohistochemistry and RT-PCR (Reverse Transcriptase-PCR) in order to disclose the patterns of p63 expression. We have observed that the full-length isoforms can be detected in non neoplastic and neoplastic lesions, while the short isoforms are only present in the neoplastic cells of invasive carcinomas. Metaplastic carcinomas of the breast are a heterogeneous group of neoplasms which exhibit varied patterns of metaplasia and differentiation. The existence of such non-modal populations harbouring distinct genetic aberrations may explain the phenotypic diversity observed within a given tumour. Intra-tumour morphological heterogeneity is not uncommon in breast cancer and it can often be appreciated in metaplastic breast carcinomas. Aim of this study was to determine the existence of intra-tumour genetic heterogeneity in metaplastic breast cancers and whether areas with distinct morphological features in a given tumour might be underpinned by distinct patterns of genetic aberrations. 47 cases of metaplastic breast carcinomas were retrieved. Out of the 47 cases, 9 had areas that were of sufficient dimensions to be independently microdissected. Our results indicate that at least some breast cancers are composed of multiple non-modal populations of clonally related cells and provide direct evidence that at least some types of metaplastic breast cancers are composed of multiple non-modal clones harbouring distinct genetic aberrations. Oncocytic tumours represent a distinctive set of lesions with typical granular cytoplasmatic eosinophilia of the neoplastic cells. Only rare example of breast oncocytic carcinomas have been reported in literature and the incidence is probably underestimated. In this study we have analysed 33 cases of oncocytic invasive breast carcinoma of the breast, selected according to morphological and immunohistochemical criteria. These tumours were morphologically classified and studied by immunohistochemistry and aCGH. We have concluded that oncocytic breast carcinoma is a morphologic entity with distinctive ultrastructural and histological features; immunohistochemically is characterized by a luminal profile, it has a frequency of 19.8%, has not distinctive clinical features and, at molecular level, shows a specific constellation of genetic aberration.

Il conflitto fra trasparenza sui mercati finanziari ed esigenza di riservatezza della società

The thesis main topic is the conflict between disclosure in financial markets and the need for confidentiality of the firm. After a recognition of the major dynamics of information production and dissemination in the stock market, the analysis moves to the interactions between the information that a firm is tipically interested in keeping confidential, such as trade secrets or the data usually covered by patent protection, and the countervailing demand for disclosure arising from finacial markets. The analysis demonstrates that despite the seeming divergence between informational contents tipically disclosed to investors and information usually covered by intellectual property protection, the overlapping areas are nonetheless wide and the conflict between transparency in financial markets and the firm’s need for confidentiality arises frequently and sistematically. Indeed, the company’s disclosure policy is based on a continuous trade-off between the costs and the benefits related to the public dissemination of information. Such costs are mainly represented by the competitive harm caused by competitors’ access to sensitive data, while the benefits mainly refer to the lower cost of capital that the firm obtains as a consequence of more disclosure. Secrecy shields the value of costly produced information against third parties’ free riding and constitutes therefore a means to protect the firm’s incentives toward the production of new information and especially toward technological and business innovation. Excessively demanding standards of transparency in financial markets might hinder such set of incentives and thus jeopardize the dynamics of innovation production. Within Italian securities regulation, there are two sets of rules mostly relevant with respect to such an issue: the first one is the rule that mandates issuers to promptly disclose all price-sensitive information to the market on an ongoing basis; the second one is the duty to disclose in the prospectus all the information “necessary to enable investors to make an informed assessment” of the issuers’ financial and economic perspectives. Both rules impose high disclosure standards and have potentially unlimited scope. Yet, they have safe harbours aimed at protecting the issuer need for confidentiality. Despite the structural incompatibility between public dissemination of information and the firm’s need to keep certain data confidential, there are certain ways to convey information to the market while preserving at the same time the firm’s need for confidentality. Such means are insider trading and selective disclosure: both are based on mechanics whereby the process of price reaction to the new information takes place without any corresponding activity of public release of data. Therefore, they offer a solution to the conflict between disclosure and the need for confidentiality that enhances market efficiency and preserves at the same time the private set of incentives toward innovation.

Il sindacato della Corte di cassazione sul travisamento della prova

Sect. 606, par. 1, e), as modified by Law 46, enacted on Februray 20th, 2006 introduced the chance to appeal to the Court of cassation in case of inconsistent reasoning and extended control on its existence and on other flaws and lack of obvious logic over the text of the contested decision, namely “to other acts the process specified in the grounds of burden”. The renewed provision seems to properly reappoint the “distortion of the evidence”, i.e. the omitted or distorted evidence that could be relevant and conclusive one, in the peculiar context of the grounds' vice. After a general review of the obligation to state reasons for judicial decisions, we analyze the innovative status of the vice of “distortion of evidence” and the conditions and the limits - defined by the law - within we can contest a resolution for illegitimacy. Then, we outline the systematic spin-off brought by the new form of sect. 606, par. 1, e) on some institutions in the code of criminal procedure. Finally, we make the role of the Court of cassation clear in the modern criminal trial, since the 2006 reform gave no definite answer on this fundamental aspect of the question.

Studio di marcatori immunoistochimici, analisi FISH e ruolo dei microRNA nelle neoplasie gliali di basso e di alto grado

Gliomas are the most common primary brain tumours. Despite advances in surgical techniques, postoperative supportive care, radiation and adjuvant systemic therapy, the life expectancy of patients with high grade glioma has remained essentially poor. Furthermore differential diagnosis among astrocytomas, oligodendrogliomas and oligoastrocytomas is very challenging and subject to inter-observer variability. The purpose of the research was: 1) to investigate a series of high grade and low grade gliomas at gene and protein (immunohistochemistry) levels to disclose possible genetic portraits of malignancy; 2) to verify the utility of Nogo-A, Olig-2 and synaptophysin in providing a correct histological diagnosis of oligodendroglioma and to investigate a possible complementary role in selecting the best areas suitable for detecting 1p/19q codeletion using FISH analysis; 3) to study the role of microRNA in high grade gliomas. In order to obtain these goals large series of brain tumors were studied with DNA microarrays, immunohistochemistry and RT-PCR The results demonstrated that: - Overexpression of IGFBP-2 and CDC20 is highly related to glioblastomas and their immunopositivity can be useful for the identification of glioblastoma in small biopsies. - Nogo-A is the most useful and specific marker in differentiating oigodendrogliomas from other gliomas. Furthermore, using a Nogo-A driven FISH analysis, it is possible to identify a larger number of 1p19q codeletions in gliomas. - microRNAs can be studied in paraffin embedded tissues better than in fresh tissues. A series of six microRNA, significatively deregulated in glioblastomas, may represent a genetic signature with prognostic and predictive value and could constitute candidates for novel anti-cancer therapeutics.

Three essays in industrial organization

This dissertation comprises three essays on the topic of industrial organization. The first essay considers how different intellectual property systems can affect the incentives to invest in R&D when innovation is cumulative. I introduce a distinction between plain and sophisticated technological knowledge, which plays a crucial role in determining how different appropriability rules affect the incentives to innovate. I argue that the positive effect of weak intellectual property regimes on the sharing of intermediate technological knowledge vanishes when technological knowledge is sophisticated, as is likely to be the case in many high tech industries. The second essay analyzes a two-sided market for news where advertisers may pay a media outlet to conceal negative information on the quality of their own product (paying positive to avoid negative) and/or to disclose negative information on the quality of their competitors products (paying positive to go negative). It is shown that whether advertisers have negative consequences on the accuracy of media reports or not, ultimately depends on the extent of correlation among advertisers products. The third essay considers the role of social learning in the diffusion of a new technology. A population of agents can choose between two risky technologies: an old one for which they know the expected outcome, and a new one for which they have only a prior. Different environments are confronted. In the benchmark case agents are isolated and can perform costly experiments to infer the quality of the new technology. In the other cases agents are settled in a network and can observe the outcomes of neighbors. We observe that in expectations the quality of the new technology may be overestimated when there is a network spread of information.

The impact of R&D in firm value across Europe

In this thesis the impact of R&D expenditures on firm market value and stock returns is examined. This is performed in a sample of European listed firms for the period 2000-2009. I apply different linear and GMM econometric estimations for testing the impact of R&D on market prices and construct country portfolios based on firms’ R&D expenditure to market capitalization ratio for studying the effect of R&D on stock returns. The results confirm that more innovative firms have a better market valuation,investors consider R&D as an asset that produces long-term benefits for corporations. The impact of R&D on firm value differs across countries. It is significantly modulated by the financial and legal environment where firms operate. Other firm and industry characteristics seem to play a determinant role when investors value R&D. First, only larger firms with lower financial leverage that operate in highly innovative sectors decide to disclose their R&D investment. Second, the markets assign a premium to small firms, which operate in hi-tech sectors compared to larger enterprises for low-tech industries. On the other hand, I provide empirical evidence indicating that generally highly R&D-intensive firms may enhance mispricing problems related to firm valuation. As R&D contributes to the estimation of future stock returns, portfolios that comprise high R&D-intensive stocks may earn significant excess returns compared to the less innovative after controlling for size and book-to-market risk. Further, the most innovative firms are generally more risky in terms of stock volatility but not systematically more risky than low-tech firms. Firms that operate in Continental Europe suffer more mispricing compared to Anglo-Saxon peers but the former are less volatile, other things being equal. The sectors where firms operate are determinant even for the impact of R&D on stock returns; this effect is much stronger in hi-tech industries.

I limiti al diritto di proprietà derivanti dagli strumenti di pianificazione urbanistica. I vincoli urbanistici.

Nella prima parte viene ricostruito il concetto di vincolo espropriativo alla luce dell’elaborazione della giurisprudenza della Corte costituzionale e della Corte EDU, giungendo alla conclusione che rientrano in tale concetto le limitazioni al diritto di proprietà che: - derivano da scelte discrezionali dell’Amministrazione non correlate alle caratteristiche oggettive del bene; - superano la normale tollerabilità nel senso che impediscono al proprietario la prosecuzione dell’uso in essere o incidono sul valore di mercato del bene in modo sproporzionato rispetto alle oggettive caratteristiche del bene e all’interesse pubblico perseguito. Ragione di fondo della teoria dei vincoli è censurare l’eccessiva discrezionalità del potere urbanistico, imponendo una maggiore obiettività e controllabilità delle scelte urbanistiche. Dalla teoria dei vincoli consegue altresì che nell’esercizio del potere urbanistico l’Amministrazione, pur potendo differenziare il territorio, deve perseguire l’obiettivo del riequilibrio economico degli interessi incisi dalle sue determinazioni. L’obbligo della corresponsione dell’indennizzo costituisce la prima forma di perequazione urbanistica. Nel terzo e nel quarto capitolo viene analizzata la giurisprudenza civile e amministrativa in tema di vincoli urbanistici, rilevandone la non corrispondenza rispetto all’elaborazione della Corte costituzionale e l’incongruità dei risultati applicativi. Si evidenzia in particolare la necessità del superamento del criterio basato sulla distinzione zonizzazioni-localizzazioni e di considerare conformative unicamente quelle destinazioni realizzabili ad iniziativa privata che in concreto consentano al proprietario di conseguire un’utilità economica proporzionata al valore di mercato del bene. Nel quinto capitolo viene analizzato il rapporto tra teoria dei vincoli e perequazione urbanistica, individuandosi il discrimine tra i due diversi istituti non solo nel consenso, ma anche nella proporzionalità delle reciproche prestazioni negoziali. Attraverso la perequazione non può essere attribuito al proprietario un’utilità inferiore a quella che gli deriverebbe dall’indennità di esproprio.

The challenges and the limitations in Life Cycle Impact Assessment for metal oxide nanoparticles, a case study on nano- TiO2

Life Cycle Assessment (LCA) is a chain-oriented tool to evaluate the environment performance of products focussing on the entire life cycle of these products: from the extraction of resources, via manufacturing and use, to the final processing of the disposed products. Through all these stages consumption of resources and pollutant releases to air, water, soil are identified and quantified in Life Cycle Inventory (LCI) analysis. Subsequently to the LCI phase follows the Life Cycle Impact Assessment (LCIA) phase; that has the purpose to convert resource consumptions and pollutant releases in environmental impacts. The LCIA aims to model and to evaluate environmental issues, called impact categories. Several reports emphasises the importance of LCA in the field of ENMs. The ENMs offer enormous potential for the development of new products and application. There are however unanswered questions about the impacts of ENMs on human health and the environment. In the last decade the increasing production, use and consumption of nanoproducts, with a consequent release into the environment, has accentuated the obligation to ensure that potential risks are adequately understood to protect both human health and environment. Due to its holistic and comprehensive assessment, LCA is an essential tool evaluate, understand and manage the environmental and health effects of nanotechnology. The evaluation of health and environmental impacts of nanotechnologies, throughout the whole of their life-cycle by using LCA methodology. This is due to the lack of knowledge in relation to risk assessment. In fact, to date, the knowledge on human and environmental exposure to nanomaterials, such ENPs is limited. This bottleneck is reflected into LCA where characterisation models and consequently characterisation factors for ENPs are missed. The PhD project aims to assess limitations and challenges of the freshwater aquatic ecotoxicity potential evaluation in LCIA phase for ENPs and in particular nanoparticles as n-TiO2.

Parola arcaica e costruzioni del moderno. I sentieri della scrittura in Julio Herrera y Reissig

L’obbiettivo del lavoro è quello di delimitare uno spazio critico che consenta di ripensare il concetto di modernità nelle culture ispanoamericane degli inizi del XX secolo. In questa direzione, si è deciso di focalizzare l’attenzione su un’opera letteraria, quella dell’uruguaiano Julio Herrera y Reissig, del tutto particolare se comparata al resto delle produzioni estetiche a essa più immediatamente contigue. Tornare a leggere Herrera y Reissig equivale, infatti, nella sostanza, a rimettere mano criticamente a tutta l’epoca modernista, interpretandola non in senso unitario, bensì plurale e frammentario. Spunto di partenza dell’analisi sono state le coordinate culturali comuni in cui quelle estetiche si sono determinate e sviluppate, per poi procedere verso una moltiplicazione di percorsi in grado di rendere conto della sostanziale discrepanza di mezzi e finalità che intercorre fra Julio Herrera y Reissig e gran parte del Modernismo a lui contemporaneo. Mantenendo come base metodologica i presupposti dell’archeologia culturale foucauldiana, è stato possibile rintracciare, nell’opera dell’uruguaiano, un eterogeneo ma costante movimento di riemersione e riutilizzo delle più svariate esperienze del pensiero – estetico e non – occidentale. Nelle particolarità d’uso a cui la tradizione è sottomessa nella scrittura di Herrera y Reissig si è reso così possibile tornare a ragionare sui punti focali dell’esperienza della modernità: il legame fra patrimonio culturale e attualità, la relazione fra sedimentazione tradizionale e novità, nonché, in definitiva, le modalità attraverso le quali alla letteratura è consentito di pensare e dire la propria storia – passata, presente e futura – e, in conseguenza, metabolizzarla, per tornare ad agire attivamente su di essa.

Strumenti finanziari partecipativi e "nuovi" canali di finanziamento delle societa' per azioni

Il lavoro affronta il tema degli strumenti finanziari partecipativi e non partecipativi che possono essere emessi dalle società per azioni, alla luce della disciplina introdotta dalla riforma del diritto societario. Lo studio è diretto a fornire un inquadramento sistematico di queste modalità di finanziamento rispetto alla dicotomia azioni-obbligazioni, anche sotto il profilo contabile, per poi individuare le conseguenti implicazioni in termini di disciplina applicabile. Affrontando il dibattito dottrinale sulla collocazione complessiva degli strumenti ibridi rispetto alle forme di finanziamento tradizionali, si sposa l’opinione secondo cui tutti gli strumenti finanziari non possono essere ricompresi in una categoria unitaria, ma occorre mantenere distinti gli strumenti finanziari partecipativi indicati dall’art. 2346, comma 6, c.c., dagli altri strumenti finanziari ex art. 2411, comma 3, c.c., riconoscendo nei primi delle modalità di raccolta assimilabili al capitale di rischio e nei secondi delle forme di provvista di capitale di debito. Il connotato distintivo tra strumenti finanziari partecipativi e non partecipativi viene individuato non nell’attribuzione di diritti amministrativi – che possono anche non essere assegnati ai titolari di strumenti di cui all’art. 2346, comma 6 – bensì nell’assenza o nella presenza di un obbligo di rimborso dell’apporto fornito all’impresa. Il lavoro esamina inoltre vari profili di disciplina di entrambe le categorie di strumenti, concentrandosi prevalentemente sui diritti patrimoniali ad essi attribuibili, tra cui la partecipazione agli utili e alle perdite e i diritti in sede di liquidazione. Infine si esaminano le previsioni recentemente introdotte dal d.l. n. 83/2012 in tema di titoli obbligazionari, al fine di valutarne l’impatto sull’impianto complessivo della disciplina vigente. In particolare, viene data attenzione alle nuove disposizioni relative alle obbligazioni subordinate e/o partecipative che possono essere emesse dalle società non quotate, mettendo in evidenza le criticità dal punto di vista sistematico in tema di possibile partecipazione agli utili degli obbligazionisti.

New routes to enantioenriched substances through small organic molecules

In this thesis we will disclose the results obtained from the diastereoisomeric salt formation (n salt, p salt and p1,n1 salt) between non-racemic trans-chrysanthemic acid (trans-ChA) and pure enantiomers of threo-2-dimethylamino-1-phenyl-1,3-propanediol (DMPP). The occurrence of p1,n1 salt formation can have profound effects on enantiomer separation of scalemic (non-racemic) mixtures. This phenomenon when accompanied by substrate self-association impedes the complete recovery of the major enantiomer through formation of an inescapable racemate cage. A synthetic sequence for the asymmetric synthesis of bicyclo[3.2.0]heptanones and bicyclo[3.2.0]hept-3-en-6-ones through a cycloaddition strategy is reported. The fundamental step is a [2+2]-cycloaddition of an enantiopure amide derived from the reaction between a set of acids and an oxazolidinone as the chiral auxiliary. The inter- and intramolecular cycloaddition of in situ-generated keteniminium salts gives bicycles with a good enantioselection. A key intermediate of Iloprost, a chemically stable and biologically active mimic of prostacyclin PGI2 is synthesized following a ‘green approach’. An example of simple optical resolution of this racemic intermediate involving the diastereoisomeric salt formation is described.

Multi-target-directed ligands: application to the Alzheimer's disease

The MTDL (multi-target-directed ligand) design strategy is used to develop single chemical entities that are able to simultaneously modulate multiple targets. The development of such compounds might disclose new avenues for the treatment of a variety of pathologies (e.g. cancer, AIDS, neurodegenerative diseases), for which an effective cure is urgently needed. This strategy has been successfully applied to Alzheimer’s disease (AD) due to its multifactorial nature, involving cholinergic dysfunction, amyloid aggregation, and oxidative stress. Despite many biological entities have been recognized as possible AD-relevant, only four achetylcholinesterase inhibitors (AChEIs) and one NMDA receptor antagonist are used in therapy. Unfortunately, such compounds are not disease-modifying agents behaving only as cognition enhancers. Therefore, MTDL strategy is emerging as a powerful drug design paradigm: pharmacophores of different drugs are combined in the same structure to afford hybrid molecules. In principle, each pharmacophore of these new drugs should retain the ability to interact with its specific site(s) on the target and, consequently, to produce specific pharmacological responses that, taken together, should slow or block the neurodegenerative process. To this end, the design and synthesis of several examples of MTDLs for combating neurodegenerative diseases have been published. This seems to be the more appropriate approach for addressing the complexity of AD and may provide new drugs for tackling the multifactorial nature of AD, and hopefully stopping its progression. According to this emerging strategy, in this work thesis different classes of new molecular structures, based on the MTDL approach, have been developed. Moreover, curcumin and its constrained analogs have currently received remarkable interest as they have a unique conjugated structure which shows a pleiotropic profile that we considered a suitable framework in developing MTDLs. In fact, beside the well-known direct antioxidant activity, curcumin displays a wide range of biological properties including anti-inflammatory and anti-amyloidogenic activities and an indirect antioxidant action through activation of the cytoprotective enzyme heme oxygenase (HO-1). Thus, since many lines of evidence suggest that oxidative stess and mitochondria impairment have a cental role in age-related neurodegenerative diseases such as AD, we designed mitochondria-targeted antioxidants by connecting curcumin analogs to different polyamine chains that, with the aid of electrostatic force, might drive the selected antioxidant moiety into mitochondria.