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Desarollo de derivados de 4-hidroxicumarina con diferente actividad farmacológica
Get PDFThis dissertation is an interdisciplinary work focused on the discovery and development of new drugs. It includes organic synthesis methodologies and pharmacological evaluation elements seeking structure-activity relationships that allow us to rationally guide the design of new structures with improved properties.
Continuing the work that has been made in our research group, we have first synthesized and studied a series of coumarin-resveratrol analogs incorporating an
hydroxyl group at the 4 position of the prototype 3-arylcoumarin. This modification allows us also to approach to other type of compounds, isoflavones,
that are very abundant in nature. Subsequently we have prepared and studied a series of other different derivatives where the hydroxyl group at the 4 position has
been replaced by a benzyloxy group. The preparation of the desired compounds has been performed by using parallel
synthesis strategies; that means efficient and easily reproducible synthetic procedures for the production of a number of products in sufficient quantities for
pharmacological evaluation. The preliminary biological essays indicate that some of the studied compounds
seems to be active against Staphylococcus Aureus and Tenacibaculum Maritimum bacterial strains. Additionally, some other compounds are inhibitors of MAO-B and they also showed an interesting antioxidant activity. The compounds tested for their cytotoxicity activity against MCF-7 and HL-60 cell lines have shown good results. The series of compounds studied allow us to establish the basic structural
requirements to modulate the pharmacological properties, opening up a very interesting research path
Isolamento e caratterizzazione chimico-strutturale di metaboliti secondari dal genere Ononis e Seseli
Get PDFIn a continuation of our research on bioactive natural products form Seseli praecox we now focused on a population growing on the island of San Pietro (Sardinia). With respect
to the population growing on limestone from Ogliastra (Sardinia) studied previously this population grows on weathered volcanic substrate and shows different morphological characteristics. Seseli sp. is a classical medicinal plant taxon and mentioned by Dioscorides as well as Galenos amongst other indications against orthopnea, chronic cough, uterine spasms and epilepsy. Orthopnea, a form of breathlessness caused by increased central and pulmonary blood volume has been associated with chronic heart failure. The phytochemical investigation of the extract obtained from the stems of S. praecox afforded five known khellactones, five furocumarines, two coumarins, two
chromone, as well as falcarinol and falarindiol and a new natural compound 5-hydroxy-6-[3-(hydroxymethyl)-4-methyl-2-pentenyl]-7-methoxy-2-methyl-4-H-cromen-4-one. Khellactones are dihydroseselin type angular pyranocumarins and have been obtained from different Apiaceae species used in local medicine as well as food. Similar to the medicinal indications of Seseli sp., Ammi visnaga (L.) Lam. is used against cardio-vascular and urological problems. Visnadine, a khellactone obtained from A. visnaga fruits was shown to inhibit Ca2+ channels ex vivo. According on these data, 5 khellactones are tested as potential inhibitors to the Ca2+ channel. Only Hyuganin D was active. Different papers suggest that pyranocoumarins could be a potential MDR reversing agent. In this thesis we remark that Hyuganin D showed ability to induces calcium transients reproducible and in the same time are able to inhibit P-gp in Rhodamine123 efflux assay in Pgp transfected MDCK cells with an effect similar to vinblastine. We are currently
developing the cytotoxicity test. We have also investigated the secondary metabolites of Ononis natrix, a small shrub
belongs to the family Legumynose (tribe Trifoleae). The infusion of its roots and flowers has been used for the treatment of some disturbances of the urinary tract, in fact have been reported to have diuretic and antirheumatic proprieties. Members of this genus has been also used in folk medicine for the treatment of jaundice, kidney stones and skins diseases. Compounds isolated from the genus Ononis have also show antibiotic, molluscicidal, antiviral activities. In this thesis we describe the isolation and
determination of the structure of three new natural product: two dihydroisocoumarins(1-1[(6,8-dihydroxy-1-oxo-3,4-dihydro-1H-isochromen-3-yl)methyl]heptyl acetate 1-[(6,8-dihydroxy-1-oxo-3,4-dihydro-1H-isochromen3 yl)methyl]-5-oxoheptyl acetate) and 4-methoxyphenyl 3-(4-methoxyphenyl)propanoate. Additionally we have isolated 12 know compounds (two flavones, four flavanones, a chalcone and six dihydrochalcones). All compounds were evaluated for their activity against Staphylococcus aureus and Candidaalbicans. The most active compound against S.aureus is 2’,6’-dihydroxy-4’-methoxydihydrochalcone (2 μg). 2’,4’-dihydroxy-6’-methoxydihydrochalcone, 1-[(6,8-
dihydroxy-1-oxo-3,4-dihydro-1H-isochromen-3-yl)methyl]heptyl
acetate and 4-methoxyphenyl 3-(4-methoxyphenyl)propanoate show a good activity against S. aureus(16 μg). Other compounds are less active than these. The most active compound against C. albicans is 7-hydroxy-8-methoxyflavone (8 μg) and 2’,4’-dihydroxy-6’-methoxy-dihydrochalcone show a good activity against C. albicans (16 μg)
Sviluppo di vettori virali per la terapia genica della β−Talassemia
Get PDFBeta−thalassemia major is a severe congenital anemi for which there is presently no curative therapy other than allogeneic hematopoietic stem cell transplantation. This therapeutic option, however, applies only to the minority of thalassemia patients who have an HLA−matched bone marrow donor. Gene therapy by the delivery of a regulated globin gene to autologous hematopoietic stem cells is an attractive alternative approach as it is in principle applicable to all thalassemic subjects. Current vectors, althougheffective in correcting thalassemia in murine models still suffer some drawbacks in terms of safety and also in terms of low titer and expression. The aim of this study was to assemble globin vectors improved in both these aspects. Modifications of the globin cassette in the intron2 and in the LCR of the beta-‐globin gene can increase the expression of the globin gene without reducing the vector titer. We also examine the variegation in the expression among the different pools of transduce cells and we suppose that the presence of sequences with chromatin opening activity among the segments of b-‐globin IVS
Use of organocatalysts in stereoselective organic synthesis
Get PDFThe main topic of thesis is the use of organocatalysis to synthesize cyclobutanones derivatives. Cyclobutanone derivatives are useful molecular building blocks for the construction of complex molecular structures. Surprisingly, however, the use of organocatalysts to functionalize cyclobutanones is rare, especially when the substrate bears substituents. In this thesis, we present four enantioselective transformations of substituted cyclobutanones which employ readily-available amino acids (or derivatives) and thiourea derivatives as organocatalysts.
- The first transformation involves enantioselective aldol reaction between 2-hydroxy-cyclobutanone with a selection of aromatic aldehyde. The results show that the 2-hydroxycyclobutanone is particularly amenable to solvent-free L-threonine-catalyzed direct aldol reactions with reasonable stereocontrol.
- After, we synthesized 2,3-disubstituted cyclobutanones through direct aldol reactions involving 3-substituted cyclobutanones and aryl aldehydes catalyzed by N-phenylsulfonyl (S)-proline and via asymmetric nitro-Michael reaction of 3-substituted cyclobutanones and several nitrostyrenes catalyzed by thiourea derivatives. In the first case the relative aldol products were obtained with an unprecedented control of all three contiguous stereocenters in the latter the relatives γ-nitro cyclobutanones were obtained in good yield but in modest enantioselectivity.
- The last case concerns the conversion of 3-substituted cyclobutanones into 4-substituted-5-hydroxy-γ-lactam using L-proline-based catalysts. This reaction involves a ring-expanding O-nitroso-aldol–cyclization domino sequence. The synthetic protocol provides access to the five-membered ring system in good yield, and the formation of two new stereogenic centers is achieved with complete stereochemical control
Strategic environmental assessment approach: governance and planning
Get PDFThe dissertation is framed within the topics of regional governance and Strategic Environmental Assessment (SEA). Compared to its relationship with governance the SEA may be defined as a set of rules, principles, techniques and tools with the function of supporting the decision making
process. The evaluation process is strategically relevant when applying the principles of environmental sustainability to regional and urban planning. SEA is a fundamental instrument for the environmental integration during the elaboration and adoption of plans; SEA offers an opportunity to bring about a real change of attitude and culture at strategic levels into strategic decision-making process; SEA, according to the Directive 2001/42/EC, provides the most adequate opportunity to integrate different regional planning methods. The dissertation mechanisms of regional governance, defined as the process involving the formation and implementation of decisions. The objective of this study is to analyse the relationships between the various stakeholders and governmental institutions, with the aim of defining in what terms, with reference to regional governance, the theoretical principles of sustainable development (in terms of managing the relationship between natural resources and economic development) can be applied to the planning phases.
The main aim is to build a framework for sequential activities in the planning process, of a new model of governance able to relate to different levels of government, from a political level to a local
level.
The Sardinian case study contains some interesting aspects of planning and evaluation processes
currently under way, which could be exported and developed further. However, it does suffer from
several inconsistencies which are highlighted by the Directive 2001/42/EC.
The innovative aspect of the research project, respect to the current planning situation of the SEA
and the planning procedures, consists in the creation of a Protocol for the integration of the two
approaches related to the construction of the plan and the activation process of SEA.
In particular in the construction of system to accompany and support the government in adapting
the plans, and secondly to support local authorities in the definition of strategic choices. Don’t exist
in Sardinia a guidance for SEA process of general plan, This Guidance is intended to be valid for all
plans from regional to urban plans by defining a decisional process where the SEA is part of the
plan, creating a process more inclusive of aspects of environmental and public consultation. The
involvement of consulting the public and authorities with environmental responsibilities is the goal
of the new model of the assessment process
Nuove e vecchie “jiating”: i cambiamenti intercorsi nell’istituzione familiare cinese a partire dal 1911
Get PDFThis job has the aim to answer at some interesting questions concerning the evolution of Chinese Family in the last century. In particular: which changes has the Chinese family gone through in the last century? After one hundred years of historical and legislative modification of the State, which peculiar elements of traditional Chinese family existing in the earlier XX century still exist?
Modern historiography has widely treated the subject “Chinese family”, but only specific subjects considered in limited time or contents have always been examined; the scenario of studies and scientific publications were lacking of a complete and wider – meaning the temporal sense – analysis, totally focused on social and legislative changes that affected China from the end of the Imperial era to this days. Considering the double track in the level of analysis undertaken - legislative and socio-political – the narrative excursus takes two directions:
Critical examination of legal texts concerning the family area from 1911 until today (IV Book – Nationalist Civil Code of 1931; Laws on Marriage of 1950 and 1980; Laws on Family Planning regarding the last thirty years of Chinese history); Interpretative study of the most important socio-political events that determined specific transitions in the attitude and the structure of the Chinese family (Movements for social renewal in 1915-1919; “New Life Movement” for restoring the Confucian traditions in 1934; Maoist-oriented Leadership of the new Communist China; Government Leadership of Deng Xiaoping, Jiang Zemin, Hu Jintao and the fight against over birth-rate). A long development process regarding the institution of Chinese family, across a century of history
Response to treatment with chemical and biological inhibitors of c-met mutated form
Get PDFc-MET is a receptor tyrosine kinase that, after binding with its ligand, hepatocyte growth factor (HGF), activates many signaling pathways, driving proliferation, motility, migration and invasion. Although c-MET is important in the control of tissue homeostasis under normal physiological
conditions, it has also been found to be aberrantly activated in human cancers via mutation, amplification or protein overexpression. Activating point mutations were identified in the kinase domain of MET, either in the germline of patients affected by hereditary papillary renal carcinoma (HPRC) or in spontaneously occurring tumors; in particular, nine missense mutations (defined METPRC mutations), leading to constitutive activation of MET protein, have been identified in HPRC families. Given the importance of MET as a target for cancer therapies, clinical trials aimed at inhibiting it through the use of tyrosine kinase inhibitors (TKIs) have recently been started. The aim of project was: (i) to evaluate if METPRC mutants are sensitive to PHA-665752 (a small kinase inhibitor of MET), (ii) if some mutants are insensitive to the inhibitor, to investigate the mechanisms responsible for resistance, (iii) to check if the resistant mutants are still sensitive to other chemicals inhibitors or monoclonal antibodies against MET, (iv) to identify activating point
mutations in human surgically resected lung cancers.
We have found that some METPRC mutants cannot be inhibited by PHA-665752. Treatment with this TKI does not alter either receptor phosphorylation or MET mutants-induced biological activities (migration, invasion, anchorage-independent growth). We showed that these mutants are
insensitive also to JNJ-38877605, a multitargeted tyrosine kinase inhibitor.. When we performed the mutational analysis on lung cancer samples, in one tumor we found the presence of one of the identified“resistant” mutations.
To determine whether the mutants resistant to PHA-665752 could be inhibited with other strategies, we treated the mutant-expressing cells with the monoclonal antibody DN30, directed against the extracellular portion of the receptor. Our results showed that DN30 was indeed able to inhibit all the METPRC mutants. In conclusion, we have identified some METPRC mutants which do not respond to the ATP competitive kinase inhibitors. Since the identified METPRC mutations are located in the kinase domain and alter its conformation; it is likely that the competitive inhibitors are unable to interact with the ATP binding site in the context of the mutated receptors; this would render these mutants "resistant" to the action of tyrosine kinase inhibitors. However, these mutated forms still remain
responsive to treatment antibodies directed against the MET extracellular portion: This observation is important since the use of monoclonal antibodies represent a therapeutic alternative for patients with tumors carrying MET mutants resistant to TKIs
Search for Millisecond Pulsars for the Pulsar Timing Array project
Get PDFPulsars are rapidly rotating highly magnetised neutron stars (i.e. ultra dense stars, where about one solar mass is concentrated in a sphere with a radius of ~ 10 km), which irradiate radio beams in a fashion similar to a lighthouse. As a consequence, whenever the beams cut our line of sight we perceive a radio pulses, one (or two) per pulsar rotation, with a frequency up to hundred of times a second. Owing to their compact nature, rapid spin and high inertia, pulsars are in general fairly stable rotators, hence the Times of Arrival (TOAs) of the pulses at a radio telescope can be used as the ticks of a clock. This holds true in particular for the subclass of the millisecond pulsars (MSPs), having a spin period smaller than the conventional limit of 30 ms, whose very rapid rotation and relatively older age provide better rotational stability than the ordinary pulsars. Indeed, some MSPs rotate so regularly that they can rival the best atomic clocks on Earth over timespan of few months or years.This feature allows us to use MSPs as tools in a cosmic laboratory, by exploiting a procedure called timing, which consists
in the repeated and regular measurement of the TOAs from a pulsar and then in the search for trends in the series of the TOAs over various timespans, from fraction of seconds to decades.For example the study of pulsars in binary systems has already provided the most stringent tests to date of General Relativity in strong gravitational fields and has unambiguously showed the occurrence of the emission of gravitational waves from a binary system comprising two massive bodies in a close orbit. In last decades a new exciting perspective has been opened, i.e. to use pulsars also for a direct detection of the so far elusive gravitational waves and thereby applying the pulsar timing for cosmological studies. In fact, the gravitational waves (GWs) going across our Galaxy pass over all the Galactic pulsars and the Earth, perturbing the spacetime at the pulsar and Earth locations, as well as anywhere along the lineofsight from the Earth and each of the pulsars. This in turn produces a modulation in the rhythm of the TOAs of the pulses from all the pulsars, with the variation in the TOAs having a strength which is proportional to the amplitude of the GW and a periodicity related to the frequency of the GW. Of course if they are caused by a common physical phenomenon (like a passingby GW), these variations of the
TOAs are expected to be somehow correlated between the various pulsars, allowing us to disentangle this effect from other effects which could mimic the occurrence of such modulation, like intrinsic irregularities in the rotation of a pulsar, changing interstellar medium along the line of sight, error in the reference clocks used for determining the TOAs and so on.The consideration of the aforementioned possible sources of additional effects which could mask the signature of a genuine GW shows that a safe direct detection of a GW cannot involve the observation and timing of a single pulsar. Instead, it has been theoretically shown that high precision timing over a 510 years dataspan of a network of suitable MSPs forming a so called Pulsar Timing Array (PTA) in which the pulsars are used as the endpoints of arms of a huge cosmic GW detector would allow us to overcome the previous problems and open the possibility of a direct detection of GWs. In particular such apparatus is able to detect GWs in the frequency range between 10 9 and 107 Hz, with the best sensitivity around the nanoHz.
Given the frequency range of operation, the most favorable source of GWs for a PTA appears to be the cosmological
background of GWs produced by the coalescence of supermassive binary blackholes in the early stages of the Universe evolution, at redshift around 12. In order to set up a suitable PTA it is necessary on one hand to search for new MSPs having the required clock stability and signal intensity, and on another hand to perform regular highprecision timing observations of the available sample, combining the results from all the pulsars with the use of a solid and well tested software, capable of revealing the genuine GW signal which is searched for. This work focuses on the first task, in an attempt to enlarge the number of suitable MSPs, in the framework of the High Time Resolution Universe (HTRU) survey for pulsars and fast radio transients, that is currently underway at the 64m Parkes Radio Telescope (NSW, Australia). This experiment has been designed in 2007 and started three years ago, with the main scope of largely increasing (possibly doubling) the total number of MSPs known in the Galactic Field (there were only about 40 of them until 2009). The enlarged sample may provide some very good MSPclocks to be added to the still relatively poor list of objects well suited for belonging to a PTA. In the first chapter of this thesis an overview of the pulsar phenomenon is given, with also a description of the timing
technique and its physical applications. The search methods that can be used to analyse the data in order to find isolated and binary pulsars are reported in the second chapter. The third chapter describes part of the work performed by me in the framework of the HTRU survey; in particular the search for MSPs in the HTRU data with a data reduction pipeline sensitive also to highly relativistic systems (i.e. to binary pulsars in close orbits). While performing the aforementioned search, it emerged the issue of the inspection of the hundreds of thousands of pulsar candidates produced by the adopted pipeline, the vast majority of them being the result of radio interferences. Therefore, a new approach has been explored for making
manageable the human intervention in the procedure of selection of the trustable candidates, namely the use of an Artificial Neural Network on the pulsar candidates. The fourth chapter is devoted to report on that. At the end, a brief summary of this thesis work is given, as well as a list of the publications, in preparation and resulting from the HTRU collaborative effort
Valutazione dello stato della pianificazione paesaggistica in Italia: criticità e prospettive
Get PDFThe thesis presents a study on the recent evolution of disciplinary, methodological and operative approaches
to Landscape planning in Italy. The adoption of the European Landscape Convention (2000), and the transposition of its principle into the Italian Legislative Decree 22 January 2004, n. 42, "Italian Code of the cultural heritage and landscape," led to a great innovation in strategic objectives in landscape planning in Italy. In this context, the introduction of the Regional Landscape Plan (PPR) redefines a new role of the planning instrument, but, in general, the regulatory framework is no able to identify operative methods and tools to be necessarily used to implement these new generation of plans. In the current situation, characterized by uncertainty in disciplinary approaches due to the recent innovation brought by the new law and by a high number of approaches developed in different time and socio-cultural contexts, it was urgent to develop a dedicated research study in order to documents on the one hand the current state of evolution through an ongoing evaluation of the state of play, and on the other propose effective operative guidelines for landscape planning. The thesis develops therefore around the main objectives outlined above, following a methodological
approach which have been proven effective in the analysis of policies for territorial government at European
level (e.g. environmental impact assessment; infrastructure for spatial information). After an in-depth critical assessment of the state of the art of the evolution of the discipline in different time and socio-cultural context of European Countries, in light of the different regulatory frameworks, the thesis proposes a comparative analysis of the implementation of landscape planning at regional level in Italy. This analysis, based on an extensive and systematic data collection on methods and tools related to
landscape planning instruments, offers an original and current State of Play for the benchmarking of the innovation process specifications. The second analysis, beside, through a structured comparative analysis, allows to identify methods and tools that have proven to ensure conditions of effective implementation of the PPR. The study, as a whole, then provides an original critical framework analysis which can be useful to scholars
and planners to clarify many of the open issues in landscape planning operative practice useful in the initial
phase of the predisposition of new plans for the territorial government
Gli Stati Uniti e il compromesso atomico indiano: tra non – allineamento e sicurezza nazionale
Get PDFThe purpose of this study was to investigate the significant role that the nuclear powers have had in the development of India's nuclear capabilities, particularly the part played by the United States. The period that was covered goes from 1947 to 1974, and it was examined by dividing it into three phases. The first includes the origins of the nuclear program, the political and historical causes which have created the conditions for the development of the project, and the aspects that allowed the technical cooperation with other countries, especially with the United States of America. The second goes through the negotiations from 1965 onwards, which led in 1968 to the
Indian decision not to sign the Nuclear Non-Proliferation Treaty, examining, in particular, the internal debate at first on the search for security guarantees from both sides: the Western countries and the Soviet Union,
later on by requesting a global nuclear disarmament. The last phase leads to the first Indian nuclear test in 1974, where the research analyses the implications on the international arena, as an introduction to the stalemate
that has characterized the next phase. Possessing nuclear weapons has always been considered a way to achieve an international status. In the case of India the proliferation was generated both by endemic situations of conflict and by the need of a stronger affirmation of its national identity. The Republic of India wanted to be recognized as a country able to play an important role on the international scene and among the non-aligned countries.
Unfortunately Indian’s nuclear test damaged the credibility of the Nuclear Non-Proliferation Treaty as it was the first country to challenge directly, deliberately and with apparent impunity, the central aim of the treaty. In this way other countries could feel encouraged to follow Indian’s
example. That was exactly what the United States and the Soviet Union feared the most: in the early sixties as the horizontal proliferation constituted a greater risk of nuclear war. A local conflict could have triggered a "domino effect" eventually involving the two superpowers, with catastrophic consequences. At the same time, the United States in the sixties, had considered the possibility to encourage and help India in acquiring unconventional weapons in an "anti-Chinese" function and continued to supply enriched uranium after its first nuclear test. One conclusion was that, even if fearing the possible repercussions on the countries of the so-called Third World and despite the damage to the image of the NPT, the first Indian nuclear test was considered by the United
States a peripheral event in the years of "appeasement". We could argue that, since India was not part of the NPT, no penalties could have been applied, but nuclear powers could have imposed disguised penalties if they had wanted to. India was a country with a strategic role because of its size and population and a point of reference in Asia, even more after the fall of Vietnam, which is the reason why Washington decided not to react harshly to its “horizontal proliferation”