Biochemistry in healthy and neoplastic human tissues: metabolic alteration revealed by HR-MAS nuclear magnetic resonance spectroscopy

This thesis is focused on the metabolomic study of human cancer tissues by ex vivo High Resolution-Magic Angle Spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. This new technique allows for the acquisition of spectra directly on intact tissues (biopsy or surgery), and it has become very important for integrated metabonomics studies. The objective is to identify metabolites that can be used as markers for the discrimination of the different types of cancer, for the grading, and for the assessment of the evolution of the tumour. Furthermore, an attempt to recognize metabolites, that although involved in the metabolism of tumoral tissues in low concentration, can be important modulators of neoplastic proliferation, was performed. In addition, NMR data was integrated with statistical techniques in order to obtain semi-quantitative information about the metabolite markers. In the case of gliomas, the NMR study was correlated with gene expression of neoplastic tissues. Chapter 1 begins with a general description of a new “omics” study, the metabolomics. The study of metabolism can contribute significantly to biomedical research and, ultimately, to clinical medical practice. This rapidly developing discipline involves the study of the metabolome: the total repertoire of small molecules present in cells, tissues, organs, and biological fluids. Metabolomic approaches are becoming increasingly popular in disease diagnosis and will play an important role on improving our understanding of cancer mechanism. Chapter 2 addresses in more detail the basis of NMR Spectroscopy, presenting the new HR-MAS NMR tool, that is gaining importance in the examination of tumour tissues, and in the assessment of tumour grade. Some advanced chemometric methods were used in an attempt to enhance the interpretation and quantitative information of the HR-MAS NMR data are and presented in chapter 3. Chemometric methods seem to have a high potential in the study of human diseases, as it permits the extraction of new and relevant information from spectroscopic data, allowing a better interpretation of the results. Chapter 4 reports results obtained from HR-MAS NMR analyses performed on different brain tumours: medulloblastoma, meningioms and gliomas. The medulloblastoma study is a case report of primitive neuroectodermal tumor (PNET) localised in the cerebellar region by Magnetic Resonance Imaging (MRI) in a 3-year-old child. In vivo single voxel 1H MRS shows high specificity in detecting the main metabolic alterations in the primitive cerebellar lesion; which consist of very high amounts of the choline-containing compounds and of very low levels of creatine derivatives and N-acetylaspartate. Ex vivo HR-MAS NMR, performed at 9.4 Tesla on the neoplastic specimen collected during surgery, allows the unambiguous identification of several metabolites giving a more in-depth evaluation of the metabolic pattern of the lesion. The ex vivo HR-MAS NMR spectra show higher detail than that obtained in vivo. In addition, the spectroscopic data appear to correlate with some morphological features of the medulloblastoma. The present study shows that ex vivo HR-MAS 1H NMR is able to strongly improve the clinical possibility of in vivo MRS and can be used in conjunction with in vivo spectroscopy for clinical purposes. Three histological subtypes of meningiomas (meningothelial, fibrous and oncocytic) were analysed both by in vivo and ex vivo MRS experiments. The ex vivo HR-MAS investigations are very helpful for the assignment of the in vivo resonances of human meningiomas and for the validation of the quantification procedure of in vivo MR spectra. By using one- and two dimensional experiments, several metabolites in different histological subtypes of meningiomas, were identified. The spectroscopic data confirmed the presence of the typical metabolites of these benign neoplasms and, at the same time, that meningomas with different morphological characteristics have different metabolic profiles, particularly regarding macromolecules and lipids. The profile of total choline metabolites (tCho) and the expression of the Kennedy pathway genes in biopsies of human gliomas were also investigated using HR-MAS NMR, and microfluidic genomic cards. 1H HR-MAS spectra, allowed the resolution and relative quantification by LCModel of the resonances from choline (Cho), phosphorylcholine (PC) and glycerolphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo 1H MRS spectroscopy. All glioma biopsies depicted an increase in tCho as calculated from the addition of Cho, PC and GPC HR-MAS resonances. However, the increase was constantly derived from augmented GPC in low grade NMR gliomas or increased PC content in the high grade gliomas, respectively. This circumstance allowed the unambiguous discrimination of high and low grade gliomas by 1H HR-MAS, which could not be achieved by calculating the tCho/Cr ratio commonly used by in vivo 1H MR spectroscopy. The expression of the genes involved in choline metabolism was investigated in the same biopsies. The present findings offer a convenient procedure to classify accurately glioma grade using 1H HR-MAS, providing in addition the genetic background for the alterations of choline metabolism observed in high and low gliomas grade. Chapter 5 reports the study on human gastrointestinal tract (stomach and colon) neoplasms. The human healthy gastric mucosa, and the characteristics of the biochemical profile of human gastric adenocarcinoma in comparison with that of healthy gastric mucosa were analyzed using ex vivo HR-MAS NMR. Healthy human mucosa is mainly characterized by the presence of small metabolites (more than 50 identified) and macromolecules. The adenocarcinoma spectra were dominated by the presence of signals due to triglycerides, that are usually very low in healthy gastric mucosa. The use of spin-echo experiments enable us to detect some metabolites in the unhealthy tissues and to determine their variation with respect to the healthy ones. Then, the ex vivo HR-MAS NMR analysis was applied to human gastric tissue, to obtain information on the molecular steps involved in the gastric carcinogenesis. A microscopic investigation was also carried out in order to identify and locate the lipids in the cellular and extra-cellular environments. Correlation of the morphological changes detected by transmission (TEM) and scanning (SEM) electron microscopy, with the metabolic profile of gastric mucosa in healthy, gastric atrophy autoimmune diseases (AAG), Helicobacter pylori-related gastritis and adenocarcinoma subjects, were obtained. These ultrastructural studies of AAG and gastric adenocarcinoma revealed lipid intra- and extra-cellularly accumulation associated with a severe prenecrotic hypoxia and mitochondrial degeneration. A deep insight into the metabolic profile of human healthy and neoplastic colon tissues was gained using ex vivo HR-MAS NMR spectroscopy in combination with multivariate methods: Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA). The NMR spectra of healthy tissues highlight different metabolic profiles with respect to those of neoplastic and microscopically normal colon specimens (these last obtained at least 15 cm far from the adenocarcinoma). Furthermore, metabolic variations are detected not only for neoplastic tissues with different histological diagnosis, but also for those classified identical by histological analysis. These findings suggest that the same subclass of colon carcinoma is characterized, at a certain degree, by metabolic heterogeneity. The statistical multivariate approach applied to the NMR data is crucial in order to find metabolic markers of the neoplastic state of colon tissues, and to correctly classify the samples. Significant different levels of choline containing compounds, taurine and myoinositol, were observed. Chapter 6 deals with the metabolic profile of normal and tumoral renal human tissues obtained by ex vivo HR-MAS NMR. The spectra of human normal cortex and medulla show the presence of differently distributed osmolytes as markers of physiological renal condition. The marked decrease or disappearance of these metabolites and the high lipid content (triglycerides and cholesteryl esters) is typical of clear cell renal carcinoma (RCC), while papillary RCC is characterized by the absence of lipids and very high amounts of taurine. This research is a contribution to the biochemical classification of renal neoplastic pathologies, especially for RCCs, which can be evaluated by in vivo MRS for clinical purposes. Moreover, these data help to gain a better knowledge of the molecular processes envolved in the onset of renal carcinogenesis.

New catalytic processes for the upgrading of furfural and 5-hydroxymethylfurfural to chemicals and fuels

The demand of energy, fuels and chemicals is increasing due to the strong growth of some countries in the developing world and the development of the world economy. Unfortunately, the general picture derived sparked an exponential increase in crude oil prices with a consequent increase of the chemical, by-products and energy, depleting the global market. Nowadays biomass are the most promising alternative to fossil fuels for the production of chemicals and fuels. In this work, the development of three different catalytic processes for the valorization of biomass-derived has been investigated. 5-hydroxymethylfurfural oxidation was studied under mild reaction condition using gold and gold/copper based catalysts synthetized from pre-formed nanoparticles and supported onto TiO2 and CeO2. The analysis conducted on catalysts showed the formation of alloys gold/copper and a strong synergistic effect between the two metals. For this reason the bimetallic catalysts supported on titania showed a higher catalytic activity respect to the monometallic catalysts. The process for the production of 2,5-bishydroxymethyl furan (BHMF) was also optimized by means the 5-hydroxymethylfurfural hydrogenation using the Shvo complex. Complete conversion of HMF was achieved working at 90 °C and 10 bar of hydrogen. The complex was found to be re-usable for at least three catalytic cycles without suffering any type of deactivation. Finally, the hydrogenation of furfural and HMF was carried out, developing the process of hydrogen transfer by using MgO as a catalyst and methanol as a hydrogen donor. Quantitative yields to alcohols have been achieved in a few hours working in mild condition: 160 °C and at autogenous pressure. The only by-products formed were light products such as CO, CO2 and CH4 (products derived from methanol transformation), easily separable from the reaction solution depressurizing the reactor.

Advanced cell culture platforms: methods for drug testing with microfluidics and microstructured devices

Advanced cell cultures are developing rapidly in biomedical research. Nowadays, various approaches and technologies are being used, however, these culturing systems present limitations from increasing complexity, requiring high costs, and not easily customization. We present two versatile and cost-effective methods for developing culturing systems that integrate 3D cell culture and microfluidic platforms. Firstly, for drug screening applications, many high-quality cell spheres of homogeneous size and shape are required. Conventional approaches usually have a dearth of control over the size and geometry of cell spheres and require sample collection and manipulation. To overcome this difficulty, in this study, hundreds of spheroids of several cell lines were generated using multi-well plates that housed our microdevices. Tumor spheroids grow at a uniform rate (in scaffolded or scaffold-free environments) and can be harvested at will. Microscopy imaging are done in real time during or after the culture. After in situ immunostaining, fluorescence imaging can be conducted while keeping the spatial distribution of spheroids in the microwells. Drug effects were successfully observed through viability, growth, and morphologic investigations. Also, we fabricated a microfluidic device suitable for directed and selective cell culture treatments. The microfluidic device was used to reproduce and confirm in vitro investigations carried out using normal culture methods, using a microglia cell line. The device layout and the syringe pump system, entirely designed in our lab, successfully allowed culture growth and medium flow regulation. Solution flows can be finely controlled, allowing treatments and immunofluorescence in one single chamber selectively. To conclude, we propose the development of two culturing platforms (microstructured well devices and in-flow microfluidic chip), which are the result of separate scientific investigations but have the primary goal of performing treatments in a reproducible manner. Our devices shall improve future studies on drug exposure testing, representing adjustable and versatile cell culture systems.

New high nuclearity carbonyl clusters

The thesis reports the synthesis, and the chemical, structural and spectroscopic characterization of a series of new Rhodium and Au-Fe carbonyl clusters. Most new high-nuclearity rhodium carbonyl clusters have been obtained by redox condensation of preformed rhodium clusters reacting with a species in a different oxidation state generated in situ by mild oxidation. In particular the starting Rh carbonyl clusters is represented by the readily available [Rh7(CO)16]3- 9 compound. The oxidized species is generated in situ by reaction of the above with a stoichiometric defect of a mild oxidizing agents such as [M(H2O)x]n+ aquo complexes possessing different pKa’s and Mn+/M potentials. The experimental results are roughly in keeping with the conclusion that aquo complexes featuring E°(Mn+/M) < ca. -0.20 V do not lead to the formation of hetero-metallic Rh clusters, probably because of the inadequacy of their redox potentials relative to that of the [Rh7(CO)16]3-/2- redox couple. Only homometallic cluster s such as have been fairly selectively obtained. As a fallout of the above investigations, also a convenient and reproducible synthesis of the ill-characterized species [HnRh22(CO)35]8-n has been discovered. The ready availability of the above compound triggered both its complete spectroscopic and chemical characterization. because it is the only example of Rhodium carbonyl clusters with two interstitial metal atoms. The presence of several hydride atoms, firstly suggested by chemical evidences, has been implemented by ESI-MS and 1H-NMR, as well as new structural characterization of its tetra- and penta-anion. All these species display redox behaviour and behave as molecular capacitors. Their chemical reactivity with CO gives rise to a new series of Rh22 clusters containing a different number of carbonyl groups, which have been likewise fully characterized. Formation of hetero-metallic Rh clusters was only observed when using SnCl2H2O as oxidizing agent because. Quite all the Rh-Sn carbonyl clusters obtained have icosahedral geometry. The only previously reported example of an icosahedral Rh cluster with an interstitial atom is the [Rh12Sb(CO)27]3- trianion. They have very similar metal framework, as well as the same number of CO ligands and, consequently, cluster valence electrons (CVEs). .A first interesting aspect of the chemistry of the Rh-Sn system is that it also provides icosahedral clusters making exception to the cluster-borane analogy by showing electron counts from 166 to 171. As a result, the most electron-short species, namely [Rh12Sn(CO)25]4- displays redox propensity, even if disfavoured by the relatively high free negative charge of the starting anion and, moreover, behaves as a chloride scavenger. The presence of these bulky interstitial atoms results in the metal framework adopting structures different from a close-packed metal lattice and, above all, imparts a notable stability to the resulting cluster. An organometallic approach to a new kind of molecular ligand-stabilized gold nanoparticles, in which Fe(CO)x (x = 3,4) moieties protect and stabilize the gold kernel has also been undertaken. As a result, the new clusters [Au21{Fe(CO)4}10]5-, [Au22{Fe(CO)4}12]6-, Au28{Fe(CO)3}4{Fe(CO)4}10]8- and [Au34{Fe(CO)3}6{Fe(CO)4}8]6- have been isolated and characterized. As suggested by concepts of isolobal analogies, the Fe(CO)4 molecular fragment may display the same ligand capability of thiolates and go beyond. Indeed, the above clusters bring structural resemblance to the structurally characterized gold thiolates by showing Fe-Au-Fe, rather than S-Au-S, staple motives. Staple motives, the oxidation state of surface gold atoms and the energy of Au atomic orbitals are likely to concur in delaying the insulator-to-metal transition as the nuclearity of gold thiolates increases, relative to the more compact transition-metal carbonyl clusters. Finally, a few previously reported Au-Fe carbonyl clusters have been used as precursors in the preparation of supported gold catalysts. The catalysts obtained are active for toluene oxidation and the catalytic activity depends on the Fe/Au cluster loading over TiO2.

Development of motion analysis protocols based on inertial sensors

The aim of this thesis was to describe the development of motion analysis protocols for applications on upper and lower limb extremities, by using inertial sensors-based systems. Inertial sensors-based systems are relatively recent. Knowledge and development of methods and algorithms for the use of such systems for clinical purposes is therefore limited if compared with stereophotogrammetry. However, their advantages in terms of low cost, portability, small size, are a valid reason to follow this direction. When developing motion analysis protocols based on inertial sensors, attention must be given to several aspects, like the accuracy of inertial sensors-based systems and their reliability. The need to develop specific algorithms/methods and software for using these systems for specific applications, is as much important as the development of motion analysis protocols based on them. For this reason, the goal of the 3-years research project described in this thesis was achieved first of all trying to correctly design the protocols based on inertial sensors, in terms of exploring and developing which features were suitable for the specific application of the protocols. The use of optoelectronic systems was necessary because they provided a gold standard and accurate measurement, which was used as a reference for the validation of the protocols based on inertial sensors. The protocols described in this thesis can be particularly helpful for rehabilitation centers in which the high cost of instrumentation or the limited working areas do not allow the use of stereophotogrammetry. Moreover, many applications requiring upper and lower limb motion analysis to be performed outside the laboratories will benefit from these protocols, for example performing gait analysis along the corridors. Out of the buildings, the condition of steady-state walking or the behavior of the prosthetic devices when encountering slopes or obstacles during walking can also be assessed. The application of inertial sensors on lower limb amputees presents conditions which are challenging for magnetometer-based systems, due to ferromagnetic material commonly adopted for the construction of idraulic components or motors. INAIL Prostheses Centre stimulated and, together with Xsens Technologies B.V. supported the development of additional methods for improving the accuracy of MTx in measuring the 3D kinematics for lower limb prostheses, with the results provided in this thesis. In the author’s opinion, this thesis and the motion analysis protocols based on inertial sensors here described, are a demonstration of how a strict collaboration between the industry, the clinical centers, the research laboratories, can improve the knowledge, exchange know-how, with the common goal to develop new application-oriented systems.

Self-Assembled Monolayers (SAMs) in Organic Field-Effect Transistors

Organic printed electronics is attracting an ever-growing interest in the last decades because of its impressive breakthroughs concerning the chemical design of π-conjugated materials and their processing. This has an impact on novel applications, such as flexible-large-area displays, low- cost printable circuits, plastic solar cells and lab-on-a-chip devices. The organic field-effect transistor (OFET) relies on a thin film of organic semiconductor that bridges source and drain electrodes. Since its first discovery in the 80s, intensive research activities were deployed in order to control the chemico-physical properties of these electronic devices and consequently their charge. Self-assembled monolayers (SAMs) are a versatile tool for tuning the properties of metallic, semi-conducting, and insulating surfaces. Within this context, OFETs represent reliable instruments for measuring the electrical properties of the SAMs in a Metal/SAM/OS junction. Our experimental approach, named Charge Injection Organic-Gauge (CIOG), uses OTFT in a charge-injection controlled regime. The CIOG sensitivity has been extensively demonstrated on different homologous self-assembling molecules that differ in either chain length or in anchor/terminal group. One of the latest applications of organic electronics is the so-called “bio-electronics” that makes use of electronic devices to encompass interests of the medical science, such as biosensors, biotransducers etc… As a result, thee second part of this thesis deals with the realization of an electronic transducer based on an Organic Field-Effect Transistor operating in aqueous media. Here, the conventional bottom gate/bottom contact configuration is replaced by top gate architecture with the electrolyte that ensures electrical contact between the top gold electrode and the semiconductor layer. This configuration is named Electrolyte-Gated Field-Effect Transistor (EGOFET). The functionalization of the top electrode is the sensing core of the device allowing the detection of dopamine as well as of protein biomarkers with ultra-low sensitivity.

Silica-Supported Gold Nanoparticles: Synthesis, Characterization and Reactivity

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).

Microfluidic device and interfacial transport: application to biomolecules and nanostructures

The aim of my dissertation is to provide new knowledge and applications of microfluidics in a variety of problems, from materials science, devices, and biomedicine, where the control on the fluid dynamics and the local concentration of the solutions containing the relevant molecules (either materials, precursors, or biomolecules) is crucial. The control of interfacial phenomena occurring in solutions at dierent length scales is compelling in nanotechnology for devising new sensors, molecular electronics devices, memories. Microfluidic devices were fabricated and integrated with organic electronics devices. The transduction involves the species in the solution which infills the transistor channel and confined by the microfluidic device. This device measures what happens on the surface, at few nanometers from the semiconductor channel. Soft-lithography was adopted to fabricate platinum electrodes, starting from platinum carbonyl precursor. I proposed a simple method to assemble these nanostructures in periodic arrays of microstripes, and form conductive electrodes with characteristic dimension of 600 nm. The conductivity of these sub-microwires is compared with the values reported in literature and bulk platinum. The process is suitable for fabricating thin conductive patterns for electronic devices or electrochemical cells, where the periodicity of the conductive pattern is comparable with the diusion length of the molecules in solution. The ordering induced among artificial nanostructures is of particular interest in science. I show that large building blocks, like carbon nanotubes or core-shell nanoparticles, can be ordered and self-organised on a surface in patterns due to capillary forces. The eective probability of inducing order with microfluidic flow is modeled with finite element calculation on the real geometry of the microcapillaries, in soft-lithographic process. The oligomerization of A40 peptide in microconfined environment represents a new investigation of the extensively studied peptide aggregation. The added value of the approach I devised is the precise control on the local concentration of peptides together with the possibility to mimick cellular crowding. Four populations of oligomers where distinguished, with diameters ranging from 15 to 200 nm. These aggregates could not be addresses separately in fluorescence. The statistical analysis on the atomic force microscopy images together with a model of growth reveal new insights on the kinetics of amyloidogenesis as well as allows me to identify the minimum stable nucleus size. This is an important result owing to its implications in the understanding and early diagnosis and therapy of the Alzheimer’s disease

Gold and the Stock Market: 3 Essays on Gold Investments

This thesis gives an overview of the history of gold per se, of gold as an investment good and offers some institutional details about gold and other precious metal markets. The goal of this study is to investigate the role of gold as a store of value and hedge against negative market movements in turbulent times. I investigate gold’s ability to act as a safe haven during periods of financial stress by employing instrumental variable techniques that allow for time varying conditional covariance. I find broad evidence supporting the view that gold acts as an anchor of stability during market downturns. During periods of high uncertainty and low stock market returns, gold tends to have higher than average excess returns. The effectiveness of gold as a safe haven is enhanced during periods of extreme crises: the largest peaks are observed during the global financial crises of 2007-2009 and, in particular, during the Lehman default (October 2008). A further goal of this thesis is to investigate whether gold provides protection from tail risk. I address the issue of asymmetric precious metal behavior conditioned to stock market performance and provide empirical evidence about the contribution of gold to a portfolio’s systematic skewness and kurtosis. I find that gold has positive coskewness with the market portfolio when the market is skewed to the left. Moreover, gold shows low cokurtosis with the market returns during volatile periods. I therefore show that gold is a desirable investment good to risk averse investors, since it tends to decrease the probability of experiencing extreme bad outcomes, and the magnitude of losses in case such events occur. Gold thus bears very important and under-researched characteristics as an asset class per se, which this thesis contributed to address and unveil.

Synthesis and surface modification of silver and gold nanoparticles. Nanomedicine applications against Glioblastoma Multiforme.

In the last decades noble metal nanoparticles (NPs) arose as one of the most powerful tools for applications in nanomedicine field and cancer treatment. Glioblastoma multiforme (GBM), in particular, is one of the most aggressive malignant brain tumors that nowadays still presents a dramatic scenario concerning median survival. Gold nanorods (GNRs) and silver nanoparticles (AgNPs) could find applications such as diagnostic imaging, hyperthermia and glioblastoma therapy. During these three years, both GNRs and AgNPs were synthesized with the “salt reduction” method and, through a novel double phase transfer process, using specifically designed thiol-based ligands, lipophilic GNRs and AgNPs were obtained and separately entrapped into biocompatible and biodegradable PEG-based polymeric nanoparticles (PNPs) suitable for drug delivery within the body. Moreover, a synergistic effect of AgNPs with the Alisertib drug, were investigated thanks to the simultaneous entrapment of these two moieties into PNPs. In addition, Chlorotoxin (Cltx), a peptide that specifically recognize brain cancer cells, was conjugated onto the external surface of PNPs. The so-obtained novel nanosystems were evaluated for in vitro and in vivo applications against glioblastoma multiforme. In particular, for GNRs-PNPs, their safety, their suitability as optoacoustic contrast agents, their selective laser-induced cells death and finally, a high tumor retention were all demonstrated. Concerning AgNPs-PNPs, promising tumor toxicity and a strong synergistic effect with Alisertib was observed (IC50 10 nM), as well as good in vivo biodistribution, high tumor uptake and significative tumor reduction in tumor bearing mice. Finally, the two nanostructures were linked together, through an organic framework, exploiting the click chemistry azido-alkyne Huisgen cycloaddition, between two ligands previously attached to the NPs surface; this multifunctional complex nanosystem was successfully entrapped into PNPs with nanoparticles’ properties maintenance, obtaining in this way a powerful and promising tool for cancer fight and defeat.

Gold Catalyzed Functionalization Of Alkynes And Allenamides

The gold(I)-catalyzed chemoselective dearomatization of β-naphthols is reported through a straightforward approach via [3,3]-sigmatropic rearrangement /allene-cyclyzation cascade processes. Easily accessed naphthyl-propargyl ethers and derivatives in this work are employed as starting materials. Delightfully, an array of deoramatized dyhydrofuryl -naphthalen-2(1H)-ones featured densely functional groups are obtained in high yields (up to 98%) in 10 min reaction time under extremely mild reaction conditions like reagent grade solvent and exposure to air. The potential of accessing to high enantioselectivety on the dearomatized dyhydrofuryl- naphthalen-2(1H)-ones is also approved by the good ee (65%) relying on (R)-xylyl- BINAP(AuCl)2. In addition, complete theoretical elucidation of the reaction pathway is also proposed which addresses a rationale for essential motivation such as regio- and chemoselectivity. Moreover, an efficient gold catalyzed intermolecular dearomatization of substituted β-naphthols with allenamides is presented here. PPh3AuTFA (5 mol %) approves the efficient dearomatively allylation protocol under mild conditions and exhibits high tolerance on substrates scope (24 examples) in good to excellent yield accompanied with high regioselectivity and stereoselectivity. Moreover, the synergistic catalytic system also highlight the synergistic function between the [PPh3Au]+ (π-acid) and TFA− (Lewis base). At last, a new chiral BINOL phosphoric acid silver salt is successfully synthesized and used as the chiral counter anion, which strongly promotes the enantioselectivity (up to 92%). At last but not least, crucially, SmI2 induced enantioselective formal synthesis of strychnine, a complex alkaloid and a classical target used to benchmark new synthetic methods is developed. Enantioselective dearomatising radical cyclisation on to the indole unit and further ET will then give organosamarium that is quenched diastereoselectively by the ester to deliver Strychnine in 7 steps.