Functional molecular hybrids based on polyoxometalates: catalytic and biological studies

Polyoxometalates (POMs) are molecular and nano-dimensional, multi-metal oxides, which have found applications in catalysis, materials science, and nano-medicine. Their general formula are: a) [MmOy]p-; b) [XxMmOy]q-, where M is the main transition metal constituent of the POM (M = Mo, V, W), O is the oxygen atom and X can be a non-metal atom, such as P, Si, As, Sb, or a different transition metal. These species are characterized by a remarkable variety, since their properties depend on elemental composition, structure, and associated counterion. In addition, it is possible to synthesize vacant POMs derivatives, with surface defects. These last structures feature coordinatively unsaturated, terminal oxygen atoms, whose nucleophilicity can be exploited to foster reactions with electrophilic organic moieties to give O-X-R bonds, where X = As, P, Si, Sn, and R = organic residue. In this way, several organic-inorganic hybrid complexes can be obtained. Thus, the merging of organic domains with POM nano-scaffolds can be exploited to design new functional molecules and materials. In particular, POM-appended organic/organometallic moieties are instrumental for advanced catalytic applications and can direct the supramolecular organization of the hybrid molecules towards extended functional nanostructures. In this thesis, we report the synthesis of hybrid POM derivatives containing luminescent chromophores (dansyl, pyrene and fluorescein), grafted as silane (with general formula (nBu4N)4[(R-Si)2O(gamma-SiW10O36)]) or chiral phosphonate (with general formula (nBu4N)3Na2[(R*PO)2(alfa-A-PW9O34)]) derivatives, with unique spectroscopic features. The use of tetrabutylammonium (nBu4N+) as counterion promotes the solubilization of the POM in CH3CN. The resulting hybrids have been characterized at the solid state and in solution by a combination of techniques (multinuclear NMR, FT-IR, ESI-MS). The characterization suggested a bis-substitution: the inorganic POM framework provides a molecular nanosurface where two molecules of the same fluorophore are anchored in a tweezer-type arrangement. Optical and chiroptical properties of the hybrid derivatives have been investigated. In particular, the fluorescence spectroscopy of the fluorophore-tagged POMs has been exploited for sensing applications towards metal ions (Cu and Pb ions) and organic molecules. A promising potential for applications in many different fields such as sensing, catalysis, nanoelectronics, and photochemical conversion of solar energy is foreseen for these luminescent systems. Moreover, due to the potential applications of POMs in medicine (many POMs exhibit antiviral, antitumoral and antibiotic activity), their association with organic domains may be also of interest to improve targeting and delivery strategies. Luminescent hybrid POMs, in particular, may couple the bio-imaging diagnostic potential with innovative therapy protocols. Thus, the assembly behavior and the stability of the luminescent hybrid POMs in physiological conditions have been investigated by means of dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The analysis showed the formation of spherical aggregates with a broad size distribution for these derivatives. Moreover, since the fluorescence of these compounds is maintained under physiological conditions, they were tracked in the cells, showing their localization in different subcellular regions. An unprecedented uptake into nucleosomes and mitochondria has been highlighted. The cytotoxicity of hybrid POMs has also been determined, showing a reduced toxicity at low doses. These results are expected to pave the way to the use of suitable POMs both as drugs and as nanodimensional scaffolds for organic drugs. Furthermore, since the preparation of hybrid derivatives could be a powerful strategy for the introduction of molecular recognition sites and the enhancement of biocompatibility, studies on the interaction between POM and hybrid POMs with important biological macromolecules (ferritin and avidin) were explored. The binding of two different kind of inorganic POMs containig Ru(IV) (RuPOM) and Eu(III) (EuPOM) respectively, on the ferritin (Ftn) has been indeed higlighted by a combined investigation, involving DLS, zeta-potential measurements, ITC (isothermal titration calorimetry), fluorimetry, CD (circular dichroism) and TEM. In particular, the complete quenching of the Trp residues luminescence, upon addition of >24 eqs of POM, likely due to energy transfer between the two domains, have shown that the POMs can be successfully attached to the Ftn by means of ionic interactions. In addition, the integrity of the protein has been estabilished by DLS and CD analysis. Moreover, a biological hybrid POM containing biotin moieties was synthesized and its interaction capability with avidin was investigated. Such study allowed to investigate the confinement of hybrid POMs in correspondence of specific protein binding sites and to design bioconjugated systems with molecular recognition properties, to be exploited in targeting therapies. A last work, developed during a short scientific mission in Dublin, in collaboration with the research group of Prof. Martin Albrecht, is also presented. We have studied a strategy for the synthesis of a POM-appended N-heterocyclic carbene (NHC) iridium complex. To this end, imidazolium moieties have been successfully grafted on the defect site of a divacant Keggin polyanion. The hybrid POM synthesized was tested in catalyzing hydrogen transfer reactions. The reduction of benzophenone to diphenyl methanol in iPrOH as solvent and hydrogen donor was used as a model reaction for probing the catalytic activity of the iridium(I) complex. In particular, full conversion after 120 min has been obtained using tBuOK as base

Selective targeting of proteins by hybrid polyoxometalates: Interaction between a bis-biotinylated hybrid conjugate and avidin

The Keggin-type polyoxometalate [\u3b3-SiW10O36]8 12 was covalently modified to obtain a bis-biotinylated conjugate able to bind avidin. Spectroscopic studies such as UV-vis, fluorimetry, circular dichroism, coupled to surface plasmon resonance technique were used to highlight the unique interplay of supramolecular interactions between the homotetrameric protein and the bis-functionalized polyanion. In particular, the dual recognition mechanism of the avidin encompasses (i) a complementary electrostatic association between the anionic surface of the polyoxotungstate and each positively charged avidin subunit and (ii) specific host-guest interactions between each biotinylated arm and a corresponding pocket on the tetramer subunits. The assembly exhibits peroxidase-like reactivity and it was used in aqueous solution for L-methionine methyl ester oxidation by H2O2. The recognition phenomenon was then exploited for the preparation of layer-by-layer films, whose structural evolution was monitored in situ by ATR-FTIR spectroscopy. Finally, cell tracking studies were performed by exploiting the specific interactions with a labeled streptavidin

A comparative study on the enzymatic biodegradability of covalently functionalized double- and multi-walled carbon nanotubes

The assessment of the biodegradability potential of carbon nanotubes (CNTs) is a fundamental point towards their applications in materials science and biomedicine. Due to the continuous concerns about the fate of such type of nanomaterials, it is very important to understand if they can undergo degradation under certain conditions and if the morphology and structure of the nanotubes play a role in this process. For this purpose we have decided to undertake a comparative study on the enzymatic degradation of CNTs with concentric multilayers. Double-walled (DW) and multi-walled (MW) CNTs of various lengths, degrees of oxidation and functionalizations using different methods were treated with horseradish peroxidase (HRP). While all tested DWCNTs resulted resistant to the biodegradation, some of the MWCNTs were partially degraded by the enzyme. We have found that short oxidized multi-walled CNTs functionalized by amidation were reduced in length and presented a high amount of defects at the end of the period of treatment with HRP. This comparative study holds its importance in the understanding of the structural changes of different types of nanotubes towards the catalytic enzymatic degradation and will help to design safer CNTs for future applications

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Functional molecular hybrids based on polyoxometalates: catalytic and biological studies

Polyoxometalates (POMs) are molecular and nano-dimensional, multi-metal oxides, which have found applications in catalysis, materials science, and nano-medicine. Their general formula are: a) [MmOy]p-; b) [XxMmOy]q-, where M is the main transition metal constituent of the POM (M = Mo, V, W), O is the oxygen atom and X can be a non-metal atom, such as P, Si, As, Sb, or a different transition metal. These species are characterized by a remarkable variety, since their properties depend on elemental composition, structure, and associated counterion. In addition, it is possible to synthesize vacant POMs derivatives, with surface defects. These last structures feature coordinatively unsaturated, terminal oxygen atoms, whose nucleophilicity can be exploited to foster reactions with electrophilic organic moieties to give O-X-R bonds, where X = As, P, Si, Sn, and R = organic residue. In this way, several organic-inorganic hybrid complexes can be obtained. Thus, the merging of organic domains with POM nano-scaffolds can be exploited to design new functional molecules and materials. In particular, POM-appended organic/organometallic moieties are instrumental for advanced catalytic applications and can direct the supramolecular organization of the hybrid molecules towards extended functional nanostructures. In this thesis, we report the synthesis of hybrid POM derivatives containing luminescent chromophores (dansyl, pyrene and fluorescein), grafted as silane (with general formula (nBu4N)4[(R-Si)2O(gamma-SiW10O36)]) or chiral phosphonate (with general formula (nBu4N)3Na2[(R*PO)2(alfa-A-PW9O34)]) derivatives, with unique spectroscopic features. The use of tetrabutylammonium (nBu4N+) as counterion promotes the solubilization of the POM in CH3CN. The resulting hybrids have been characterized at the solid state and in solution by a combination of techniques (multinuclear NMR, FT-IR, ESI-MS). The characterization suggested a bis-substitution: the inorganic POM framework provides a molecular nanosurface where two molecules of the same fluorophore are anchored in a tweezer-type arrangement. Optical and chiroptical properties of the hybrid derivatives have been investigated. In particular, the fluorescence spectroscopy of the fluorophore-tagged POMs has been exploited for sensing applications towards metal ions (Cu and Pb ions) and organic molecules. A promising potential for applications in many different fields such as sensing, catalysis, nanoelectronics, and photochemical conversion of solar energy is foreseen for these luminescent systems. Moreover, due to the potential applications of POMs in medicine (many POMs exhibit antiviral, antitumoral and antibiotic activity), their association with organic domains may be also of interest to improve targeting and delivery strategies. Luminescent hybrid POMs, in particular, may couple the bio-imaging diagnostic potential with innovative therapy protocols. Thus, the assembly behavior and the stability of the luminescent hybrid POMs in physiological conditions have been investigated by means of dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The analysis showed the formation of spherical aggregates with a broad size distribution for these derivatives. Moreover, since the fluorescence of these compounds is maintained under physiological conditions, they were tracked in the cells, showing their localization in different subcellular regions. An unprecedented uptake into nucleosomes and mitochondria has been highlighted. The cytotoxicity of hybrid POMs has also been determined, showing a reduced toxicity at low doses. These results are expected to pave the way to the use of suitable POMs both as drugs and as nanodimensional scaffolds for organic drugs. Furthermore, since the preparation of hybrid derivatives could be a powerful strategy for the introduction of molecular recognition sites and the enhancement of biocompatibility, studies on the interaction between POM and hybrid POMs with important biological macromolecules (ferritin and avidin) were explored. The binding of two different kind of inorganic POMs containig Ru(IV) (RuPOM) and Eu(III) (EuPOM) respectively, on the ferritin (Ftn) has been indeed higlighted by a combined investigation, involving DLS, zeta-potential measurements, ITC (isothermal titration calorimetry), fluorimetry, CD (circular dichroism) and TEM. In particular, the complete quenching of the Trp residues luminescence, upon addition of >24 eqs of POM, likely due to energy transfer between the two domains, have shown that the POMs can be successfully attached to the Ftn by means of ionic interactions. In addition, the integrity of the protein has been estabilished by DLS and CD analysis. Moreover, a biological hybrid POM containing biotin moieties was synthesized and its interaction capability with avidin was investigated. Such study allowed to investigate the confinement of hybrid POMs in correspondence of specific protein binding sites and to design bioconjugated systems with molecular recognition properties, to be exploited in targeting therapies. A last work, developed during a short scientific mission in Dublin, in collaboration with the research group of Prof. Martin Albrecht, is also presented. We have studied a strategy for the synthesis of a POM-appended N-heterocyclic carbene (NHC) iridium complex. To this end, imidazolium moieties have been successfully grafted on the defect site of a divacant Keggin polyanion. The hybrid POM synthesized was tested in catalyzing hydrogen transfer reactions. The reduction of benzophenone to diphenyl methanol in iPrOH as solvent and hydrogen donor was used as a model reaction for probing the catalytic activity of the iridium(I) complex. In particular, full conversion after 120 min has been obtained using tBuOK as base.I poliossometallati (POMs) sono una classe di composti a base di ossidi polianionici discreti che presentano potenzialità di utilizzo in campi diversi, quali la catalisi, la scienza dei materiali e la medicina. Tali composti possono essere rappresentati da due formule generali: (a) [MmOy]p- isopolianioni; (b)[XxMmOy]q- eteropolianioni, dove M è un metallo delle serie di transizione (solitamente V, Mo o W) mentre X può essere un non metallo (P, Si, Ge, As, Sb, Te, etc.), o un diverso metallo di transizione. La diversità strutturale e di composizione che caratterizza i POMs, si riflette in un ampio spettro di proprietà, controllabili a livello molecolare, che coinvolgono forma, potenziale redox, distribuzione della carica superficiale, acidità e solubilità. In particolare, una delle possibili modificazioni della struttura di un poliossometallato consiste nella preparazione di un complesso vacante. Poichè tali derivati presentano dei difetti strutturali sulla loro superficie, caratterizzati dalla presenza di atomi di ossigeno con reattività nucleofila, possono essere sfruttati per preparare complessi ibridi organici-inorganici. Infatti, gli atomi di ossigeno che si trovano in prossimità della lacuna vengono funzionalizzati mediante reazioni con reagenti elettrofili per dare legami O-X-R, dove X = As, P, Si, Sn, e R = residuo organico. In questo modo, la funzionalizzazione di POMs con residui organici consente lo sviluppo di molecole e materiali ibridi che possono presentare diverse funzionalità. Per esempio, l'associazione di residui organici/organometallici ai poliossoanioni ha consentito lo sviluppo di aggregati supramolecolari estesi e di sistemi innovativi con applicazioni catalitiche bifunzionali e avanzate. Sulla base di queste premesse, in questo lavoro di tesi, sono state quindi studiate nuove strategie di sintesi, per la preparazione di derivati ibridi luminescenti basati su poliossometallati contenenti cromofori, quali dansile, pirene e fluoresceina e legati covalentemente al POM come organosilani (con formula generale (nBu4N)4[(R-Si)2O(gamma-SiW10O36)]) o come fosfonati chirali (con formula generale (nBu4N)3Na2[(R*PO)2(alfa-A-PW9O34)]). Nella strategia di funzionalizzazione, l’uso di un sale di tetrabutilammonio (nBu4NBr) promuove la solubilizzazione del POM in CH3CN. I derivati ibridi ottenuti sono stati caratterizzati allo stato solido ed in soluzione utilizzando una combinazione di tecniche diverse (NMR multinucleare, FT-IR, ESI-MS). La caratterizzazione ha suggerito una bis-funzionalizzazione dello scaffold inorganico: due molecole dello stesso fluoroforo organico sono ancorate sulla superficie del POM secondo un arrangiamento a tweezer. Sono state, quindi, studiate le proprietà ottiche e chiroottiche dei derivati ibridi luminescenti preparati e, in particolare, mediante indagini di fluorescenza, è stato possibile studiare la loro capacità come sensori verso ioni metallici (Cu2+ e Pb2+) e molecole organiche. I sistemi luminescenti proposti potranno essere utilizzati in diversi ambiti applicativi: sensoristica, catalisi, nanoelettronica, e fotochimica. Inoltre, considerando il potenziale utilizzo dei POMs in ambito biomedico, che include possibile attività antibatterica, antivirale e antitumorale, la loro associazione con domini organici e leganti è di interesse anche per disegnare nuove strategie di delivery e di targeting. In particolare, POMs ibridi luminescenti, possono essere utilizzati per il bio-imaging, consentendo anche lo sviluppo di protocolli terapeutici innovativi. A tale proposito, quindi, sono stati investigati i fenomeni di aggregazione e la stabilità dei poliossanioni in soluzione fisiologica mediante indagini di dynamic light scattering (DLS), microscopia a scansione elettronica (SEM) e microscopia a trasmissione elettronica (TEM). Le analisi hanno permesso di evidenziare, per tali derivati, la formazione di aggregati sferici con un' amplia distribuzione delle dimensioni. Inoltre, poichè la luminescenza di questi sistemi viene mantenuta anche in condizioni fisiologiche, essi sono stati veicolati all'interno delle cellule, e localizzati in diverse regioni subcellulari, come nei nucleosomi e nei mitocondri. Studi dell' attività biologica dei POMs ibridi hanno, in seguito, mostrato una ridotta tossicità a basse dosi. Questi risultati sono molto promettenti in quanto potrebbero aprire la strada all' utilizzo di POM ibridi, come farmaci o supporti biologici per molecole bioattive, in nanomedicina. Poichè, inoltre, la preparazione di derivati ibridi potrebbe essere una potente strategia per l'introduzione di siti di riconoscimento molecolare e il miglioramento della biocompatibilità del derivato stesso, sono stati condotti anche studi di interazione tra POMs e POMs ibridi con importanti macromolecole biologiche, come la ferritina e l'avidina. Ad esempio, abbiamo studiato l' interazione ionica fra due diversi tipi di POM, contenenti rispettivamente Ru(IV) (RuPOM) e Eu(III) (EuPOM), con la proteina ferritina (Ftn) mediante la combinazione di diverse tecniche che hanno incluso: DLS, zeta-potential, ITC (calorimetria isotermica di titolazione), fluorimetria, CD (dicroismo circolare) e TEM. In particolare, abbiamo osservato il completo quenching della luminescenza dei residui di triptofano, in seguito all' aggiunta di >24 equivalenti di POM, dovuto, probabilmente, a trasferimenti energetici tra il POM e la macromolecola. Infine, l'integrità della proteina è stata verificata mediante analisi DLS e CD. Inoltre, è stato preparato un POM ibrido biologico contenente due molecole di biotina, al fine di valutare la sua capacità di interazione con la proteina avidina. In particolare, questo tipo di studio ha permesso di investigare la possibilità di confinare POM ibridi in corrispondenza di siti specifici di legame delle proteina e di esplorare la progettazione di nuovi sistemi bioconiugati con proprietà di riconoscimento molecolare, sfruttabili in terapie di targeting. Infine, è stata studiata una strategia di sintesi di un complesso di iridio, contenente come legante un poliossoanione ibrido funzionalizzato con un gruppo imidazolico. Questo lavoro è stato svolto nel laboratori di ricerca del Prof. Martin Albrecht presso University College of Dublin, Dublino, Irlanda. In questo caso, Il POM ibrido, preparato è stato sperimentato nella riduzione di gruppi carbonilici, mediante trasferimento di atomi di idrogeno da agenti riducenti sacrificali (iPrOH). La riduzione di benzofenone a difenil metanolo in iPrOH è stata, quindi, utilizzata come reazione modello per investigare l'attività catalitica del complesso. In particolare, è stato possibile ottenere una conversione completa dopo 120 min, utilizzando tBuOK come base

Heterogeneous acidic catalysts for the tetrahydropyranylation of alcohols and phenols in green ethereal solvents

The application of heterogeneous catalysis and green solvents to the set up of widely employed reactions is a challenge in contemporary organic chemistry. We applied such an approach to the synthesis and further conversion of tetrahydropyranyl ethers, an important class of compounds widely employed in multistep syntheses. Several alcohols and phenols were almost quantitatively converted into the corresponding tetrahydropyranyl ethers in cyclopentyl methyl ether or 2-methyltetrahydrofuran employing NH4HSO4 supported on SiO2 as a recyclable acidic catalyst. Easy work up of the reaction mixtures and the versatility of the solvents allowed further conversion of the reaction products under one-pot reaction conditions

Transfer Hydrogenation Catalysis by a N-Heterocyclic Carbene Iridium Complex on a Polyoxometalate Platform

A divacant Keggin polyanion has been decorated with a N-heterocyclic carbene (NHC) iridium(I) organometallic complex to provide a molecular model of an Ir-based supported catalyst. The characterization of the hybrid compound has been performed by multinuclear NMR spectroscopy, infrared spectroscopy, cyclic voltammetry, and mass spectroscopy, and the results are in agreement with a bisfunctionalization of the polyoxometalate scaffold. The resulting supported homogeneous complex has been successfully used to catalyze the transfer hydrogenation from iPrOH to benzophenone [with a turnover number (TON) of 680 and a turnover frequency (TOF) of up to 540 h\u20131]

Hybrid Polyoxometalates: Merging Organic and Inorganic Domains for Enhanced Catalysis and Energy Applications

Organic\u2013inorganic hybrids based on polyoxometalate scaffolds(POMs) are a unique class of molecular metal-oxides featuring a composite surface, whereby the merging of complementary domains stimulates new functions and enhances performances. The interaction between the organic and inorganic components can be designed via covalent and/or non-covalent strategies, yielding novel molecular systems with key applications in catalysis and materials science. Selected examples of such a rewarding approach will be illustrated, including the synthesis of tailored POM-based catalysts, and their application in homogeneous systems and on electrocatalytic surfaces for water splitting and renewable energy production

Optically Active Polyoxotungstates Bearing Chiral Organophosphonate Substituents

Divacant Keggin-type polyoxotungstates [\u3b3-XW10O36]8\u2013 with X = Si or Ge, were functionalized with chiral phosphoryl groups. The hybrid compounds [(R*PO)2(\u3b3-XW10O36)]4\u2013 with R = N-protected aminoalkyl groups or O-protected amino acid derivatives, were isolated. The solution characterization of the products was performed by different techniques: 183W, 31P, 13C, and 1H NMR spectroscopy, electrospray ionization mass spectrometry, UV/Vis spectroscopy, and circular dichroism (CD). The experimental data confirm the covalent grafting of the organic moieties onto the polyanionic surface. A chirality transfer, from the pendant organic arm to the inorganic framework is apparent from CD studies. Multiple Cotton effects were observed in the region of charge-transfer transitions pertaining to W\u2013O bonds. Furthermore, the 183W NMR spectra are consistent with the expected C2 symmetry, resulting from introduction of two organic stereocenters. The title complexes were used in the presence of hydrogen peroxide to perform the oxidation of methyl p-tolyl sulfide. Implications for the design of enantioselective catalysts based on these derivatives are discussed