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En este PID se propone la recopilación, creación y almacenaje de contenido virtual que permita generar de manera automática, equilibrada, objetiva e inclusiva pruebas para evaluar las prácticas de laboratorio de Química Orgánica del grado en Farmacia

Fully substituted peptide/[60]fullerene hexakis‐adducts offer an excellent opportunity for multivalent protein recognition. In contrast to monofunctionalized fullerene hybrids, peptide/[60]fullerene hexakis‐adducts display multiple copies of a peptide in close spatial proximity and in the three dimensions of space. High affinity peptide binders for almost any target can be currently identified by in vitro evolution techniques, often providing synthetically simpler alternatives to natural ligands. However, despite the potential of peptide/[60]fullerene hexakis‐adducts, these promising conjugates have not been reported to date. Here we present a synthetic strategy for the construction of 3D multivalent hybrids that are able to bind with high affinity the E‐selectin. The here synthesized fully substituted peptide/[60]fullerene hybrids and their multivalent recognition of natural receptors constitute a proof of principle for their future application as functional biocompatible materials., Depto. de Química Orgánica, Fac. de Ciencias Químicas, TRUE, pub

Since WHO has declared the COVID-19 outbreak a global pandemic, nearly seven million deaths have been reported. This efficient spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is facilitated by the ability of the spike glycoprotein to bind multiple cell membrane receptors. Although ACE2 is identified as the main receptor for SARS-CoV-2, other receptors could play a role in viral entry. Among others, C-type lectins such as DC-SIGN are identified as efficient trans-receptor for SARS-CoV-2 infection, so the use of glycomimetics to inhibit the infection through the DC-SIGN blockade is an encouraging approach. In this regard, multivalent nanostructures based on glycosylated [60]fullerenes linked to a central porphyrin scaffold have been designed and tested against DC-SIGN-mediated SARS-CoV-2 infection. First results show an outstanding inhibition of the trans-infection up to 90%. In addition, a deeper understanding of nanostructure-receptor binding is achieved through microscopy techniques, high-resolution NMR experiments, Quartz Crystal Microbalance experiments, and molecular dynamic simulations., Depto. de Química Orgánica, Fac. de Ciencias Químicas, TRUE, pub

El objetivo del proyecto es introducir la indagación guiada en el Laboratorio de Química Orgánica II. Supone la modificación de las prácticas, elaboración del material docente y creación de una sesión de búsqueda bibliográfica online.

Fully substituted peptide/[60]fullerene hexakis-adducts offer an excellent opportunity for multivalent protein recognition. In contrast to monofunctionalized fullerene hybrids, peptide/[60]fullerene hexakis-adducts display multiple copies of a peptide in close spatial proximity and in the three dimensions of space. High affinity peptide binders for almost any target can be currently identified by in vitro evolution techniques, often providing synthetically simpler alternatives to natural ligands. However, despite the potential of peptide/[60]fullerene hexakis-adducts, these promising conjugates have not been reported to date. Here we present a synthetic strategy for the construction of 3D multivalent hybrids that are able to bind with high affinity the E-selectin. The here synthesized fully substituted peptide/[60]fullerene hybrids and their multivalent recognition of natural receptors constitute a proof of principle for their future application as functional biocompatible materials.

Este proyecto tiene como objetivo llevar a cabo un cambio conceptual del Laboratorio de Química Orgánica II, introduciendo métodos del aprendizaje mediante indagación guiada (“inquiry-guided learning”). Se ha desarrollado un aprendizaje centrado en el estudiante, que requiere que los alumnos realicen sus propias hipótesis, planifiquen su experimento, reflexionen y tomen decisiones durante el desarrollo de cada sesión. Se han utilizado como estrategias principales: 1) Diseño de una práctica piloto basada en los conceptos del aprendizaje mediante indagación guiada. Dicha práctica es diferente para cada alumno, lo que ha supuesto contar con una reserva de 12-15 prácticas diferentes previamente ensayadas. 2) Diseño y elaboración del material de laboratorio necesario para transformar las prácticas ya existentes en formato expositivo en experimentos basados en indagación, planteando preguntas que los alumnos deben responder a lo largo del experimento, sin proporcionarles previamente los resultados esperados, sino promoviendo un aprendizaje activo que integra los nuevos conceptos inferidos a partir de un verdadero proceso de experimentación e investigación. 3) Promover la discusión científica de los resultados introduciendo al final de la sesión una puesta en común con un alto componente de evaluación entre iguales (“peer-assessment”). 4) Con el fin de tutorizar el papel del profesor en este modelo de aprendizaje, se ha desarrollado una guía de ayuda al profesor. 5) Por último, se han realizado encuestas de evaluación para recibir la retroalimentación necesaria de los profesores y alumnos que se han enfrentado a esta nueva metodología en nuestro Departamento.

Multivalent ligand presentation is a powerful strategy for the development of specific binders and inhibitors. Peptide/[60]fullerene hybrids have now been synthesized that exploit the complete substitution of the fullerene scaffold to afford globular structures presenting twelve copies of a peptide ligand for the recognition of E-selectin. Fully substituted peptide/[60]fullerene hexakis-adducts offer an excellent opportunity for multivalent protein recognition. In contrast to monofunctionalized fullerene hybrids, peptide/[60]fullerene hexakis-adducts display multiple copies of a peptide in close spatial proximity and in the three dimensions of space. High affinity peptide binders for almost any target can be currently identified by in vitro evolution techniques, often providing synthetically simpler alternatives to natural ligands. However, despite the potential of peptide/[60]fullerene hexakis-adducts, these promising conjugates have not been reported to date. Here we present a synthetic strategy for the construction of 3D multivalent hybrids that are able to bind with high affinity the E-selectin. The here synthesized fully substituted peptide/[60]fullerene hybrids and their multivalent recognition of natural receptors constitute a proof of principle for their future application as functional biocompatible materials

A set of BODIPY‐carboranyl dyads synthesized by a Sonogashira cross‐coupling reaction, where different C‐substituted ortho‐ and meta‐carboranyl fragments have been linked to a BODIPY fluorophore is described. Chemical, photophysical and physicochemical analyses are presented, including NMR and SXRD experiments, optical absorption/emission studies and log P measurements. These studies, supported by DFT computations (M06‐2X/6‐31G**) provide an explanation to the largely divergent cell income that these fluorescent carboranyl‐based fluorophores display, for which a structural or physicochemical explanation remains elusive. By studying the cell uptake efficiency and subcellular localization for our set of dyads on living HeLa cells, we tracked the origins of these differences to significant variations in their static dipole moments and partition coefficients, which tune their ability to interact with lipophilic microenvironments in cells. Remarkably, m‐carboranyl‐BODIPY derivatives with a higher lipophilicity are much better internalised by cells than their homologous with o‐carborane, suggesting that m‐isomers are potentially better theranostic agents for in vitro bioimaging and boron carriers for BNCT.

Amphiphilic triblock terpolymers have attractive applications in the preparation of nanoparticles with controlled morphology. An additional level of morphology control can be provided by reactive blocks, whose interactions with the solvent vary under different stimuli. In this work, we synthesized a triblock terpolymer (poly(acrylic acid)-b-poly(4-hydroxystyrene)-b-poly{1-[4-(1-methyl-1,2-dicarba-closo-dodecaborane-2-yl methyl)-phenyl]ethylene}) (PAA-b-PHS-b-PSC) containing carboranes as pendant groups by reversible addition fragmentation chain transfer (RAFT) polymerization and subsequently studied its behavior in aqueous solution. Once the nanoparticles were formed, the solubility of the second and third blocks was changed via pH and CsF reactions, respectively. The resulting micelles work as an ON/OFF system, using changes in fluorescence intensity at different pH values., Czech Science Foundation, MINECO, Generalitat de Catalunya, Depto. de Química Orgánica, Fac. de Ciencias Químicas, TRUE, pub

A small library of carborane-BODIPY/aza-BODIPY dyads were efficiently synthesized by means of a novel convergent synthetic approach, the key step of which is a Pd-catalyzed Heck coupling reaction. The structural characterization and photoluminescence properties of the newly synthesized dyads were evaluated. The presence of the carborane did not significantly alter the photophysical patterns of the BODIPY or aza-BODIPY in the final fluorophores, but it produced a decrease of the emission fluorescent quantum yields that was in the range from 1.4 % for aza-BODIPY to 48 % for BODIPY-dyads. The carborane-BODIPY dyads were successfully incorporated into cells, especially compounds 2, 4 and 13, demonstrating their cytoplasmic localization. The fluorescent and biocompatibility properties make these compounds good candidates for in vitro cell tracking.

Within the cell nucleus, in the nucleoli, ribosomal RNAs are synthesized and participate in several biological processes. To better understand nucleoli-related processes, their visualization is often required, for which specific markers are needed. Herein, we report the design of novel fluorescent organotin compounds derived from 4-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)benzohydrazide and their cytoplasm and nucleoli staining of B16F10 cells in vitro. Tin compounds bearing an aliphatic carbon chain (-C12 H25 ) and an electron-donating group (-OH) were prepared, and the latter could be derivatized to bear the boron cluster anions [B12 H12 ]2- and [3,3'-Co(1,2-C2 B9 H11 )2 ]- (COSAN). All of the conjugates have been fully characterized and their luminescence properties have been assessed. In general, they show good quantum yields in solution (24-49 %), those for the COSAN derivatives being lower. Remarkably, the linking of [B12 H12 ]2- and COSAN to the complexes made them more soluble, without being detrimental to their luminescence properties. Living B16F10 cells were treated with all of the compounds to determine their fluorescence staining properties; the compounds bearing the aliphatic chain showed a reduced staining capacity due to the formation of aggregates. Notably, the complexes bearing different boron clusters showed different staining effects; those bearing [B12 H12 ]2- showed extraordinary staining of the nucleoli and cytoplasm, whereas those bearing COSAN were only detected in the cytoplasm. The remarkable fluorescence staining properties shown by these organotin compounds make them excellent candidates for fluorescence bioimaging in vitro.

The synthesis and spectroscopic characterization of the first set of tetrakis{[(p-dodecacarboranyl)methyl]stilbenyl}ethylenes (TDSE), substituted either with a methyl or a phenyl group in the 2-position (Ccluster) of the ortho-carborane, are described. The complex absorption properties are elucidated by TD-DFT calculations, stressing the importance of through-bond conjugation. Enhanced conjugation and restriction of the conformational space are identified as the main factors for boosted luminescence properties in solution, compared with the tetraphenylethylene (TPE) core, effectively reducing internal conversion (IC). IC is further reduced when aggregate suspensions of our compounds are formed in water, providing highly luminescent materials of quasi-isolated (very weakly interacting) emitters., Ministerio de Economía y Competitividad(España), Generalitat de Catalunya, Universidad Nacional Autónoma de México, Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, TRUE, pub

The synthesis and spectroscopic characterization of the first set of tetrakis{[(p-dodecacarboranyl)methyl]stilbenyl}ethylenes (TDSE), substituted either with a methyl or a phenyl group in the 2-position (Ccluster) of the ortho-carborane, are described. The complex absorption properties are elucidated by TD-DFT calculations, stressing the importance of through-bond conjugation. Enhanced conjugation and restriction of the conformational space are identified as the main factors for boosted luminescence properties in solution, compared with the tetraphenylethylene (TPE) core, effectively reducing internal conversion (IC). IC is further reduced when aggregate suspensions of our compounds are formed in water, providing highly luminescent materials of quasi-isolated (very weakly interacting) emitters.

Two novel styrene-containing meta-carborane derivatives substituted at the second carbon cluster atom (Cc) with either a methyl (Me) or a phenyl (Ph) group are introduced herein along with a new set of stilbene-containing ortho- (o-) and meta- (m-) carborane dyads. The latter set of compounds have been prepared from styrene-containing carborane derivatives via a Heck coupling reaction. High regioselectivity has been achieved for these compounds by using a combination of palladium complexes [Pd2(dba)3]/[Pd(t-Bu3P)2] as a catalytic system, yielding exclusively E isomers. All compounds have been fully characterised and the crystal structures of seven of them were analysed by X-ray diffraction. The absorption spectra of these compounds are similar to those of their respective fluorophore groups (styrene or stilbene), showing a very small influence of the substituent (Me or Ph) linked to the second Cc atom or the cluster isomer (o- or m-). On the other hand, fluorescence spectroscopy revealed high emission intensities for Me-o-carborane derivatives, whereas their Ph-o-carborane analogues evidenced an almost total lack of fluorescence, confirming the significant role of the substituent bound to the adjacent Cc in o-carboranes. In contrast, all the m-carborane derivatives display similar photoluminescence (PL) behavior regardless of the substituent attached to the second Cc, demonstrating its small influence on emission properties. Additionally, m-carborane derivatives are significantly more fluorescent than their o-counterparts, reaching quantum yield values as high as 30.2%. Regarding solid state emission, only stilbene-containing Ph-o-carborane derivatives, which showed very low fluorescence in solution, exhibited notable PL emission in films attributed to aggregation-induced emission. DFT calculations were performed to successfully complement the photoluminescence studies, supporting the experimentally observed photophysical behavior of the styrene and stilbene-contain, Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, “Severo Ochoa” Program for Centers of Excellence in R&D, Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, TRUE, pub

An efficient process to produce boron cluster-graphene oxide nanohybrids that are highly dispersible in water and organic solvents is established for the first time. Dispersions of these nanohybrid materials in water were extraordinarily stable after one month. Characterization of hybrids after grafting of appropriate cobaltabisdicarbollide and closo-dodecaborate derivatives onto the surface of graphene oxide (GO) was done by FT-IR, XPS, and UV/Vis. Thermogravimetric analysis (TGA) clearly shows a higher thermal stability for the modified-GO nanohybrids compared to the parent GO. Of particular note, elemental mapping by energy-filtered transmission electron microscopy (EFTEM) reveals that a uniform decoration of the graphene oxide surface with the boron clusters is achieved under the reported conditions. Therefore, the resulting nanohybrid systems show exceptional physico-chemical and thermal properties, paving the way for an enhanced processability and further expanding the range of application for graphene-based materials., Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, TRUE, pub

A set of triads in which o- and m-carborane clusters are bonded to two stilbene units through Ccluster−CH2 bonds was synthesized, and their structures were confirmed by X-ray diffraction. A study on the influence of the o- and m- isomers on the absorption and photoluminescence properties of the stilbene units in solution revealed no charge-transfer contributions in the lowest excited state, as confirmed by (TD)DFT calculations. The presence of one or two B−I groups in m-carborane derivatives does not affect the emission properties of the stilbenes in solution, probably due to the rather large distance between the iodo substituents and the fluorophore. Nevertheless, a significant redshift of the photoluminescence (PL) emission maximum in the solid state (thin films and powder samples) compared to solution was observed; this can be traced back to PL sensitization, most probably due to more densely packed stilbene moieties. Remarkably, the PL absolute quantum yields of powder samples are significantly higher than those in solution, and this was attributed to the restricted environment and the aforementioned sensitization. Thus, the bonding of the carborane clusters to two stilbene units preserves their PL behavior in solution, but produces significant changes in the solid state. Furthermore, iodinated species can be considered to be promising precursors for theranostic agents in which both imaging and therapeutic functions could possibly be combined., Generalitat de Cataluya, Campus of InternationalExcellence (CEI)UAM+CSIC, COFUND program AMAROUT, “Severo Ochoa”Programfor Centers of Excellence in R&D, Ministerio de Economía y Competitividad(España), Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, TRUE, pub

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018, En el trabajo presentado en esta tesis, se continúa con 2 líneas de trabajo iniciadas en el Grupo de Química Inorgánica y Catálisis del Instituto de Ciencias Materiales de Barcelona (ICMAB-CSIC), basadas en el desarrollo de nuevos derivados de boro con propiedades fotoluminiscentes y la preparación de sistemas de alto contenido en boro. Se ha avanzado en ambas líneas de investigación, por ello la sección de resultados y discusión se divide en las siguientes dos partes: ➢Resultados y discusión I: Desarrollo y studio fotofísico de carboranos que incorporan fluoróforos Esta primera parte consta de 3 capítulos que describen la síntesis de derivados de orto- y meta-carborano enlazados a grupos estilbeno. Las moléculas preparadas han sido completamente caracterizadas por las técnicas espectroscópicas usuales y difracción de rayos-X cuando ha sido posible. Se han estudiado las propiedades fotofísicas y los resultados fueron completados con algunos cálculos teóricos. Los Capítulos 3 y 4 describen las rutas sintéticas para obtener estilbenos sustituidos con 1 o 2 clústeres de boro y la posterior preparación de carboranos sustituidos con 2 estilbenos. Para ello, se han llevado a cabo reacciones de sustitución nucleofílica y electrofílica, además de acoplamientos por Heck. Los resultados reflejan el importante papel que juega la naturaleza del carborano en el comportamiento fotofísico del estilbeno, tanto en disolución como estado sólido. En el Capítulo 5, hemos preparado moléculas con un núcleo de octavinil-POSS funcionalizado con ocho derivados de carborano a través de un grupo vinil-estilbeno. Los compuestos han mostrado una alta estabilidad térmica y, una gran intensidad de emisión fluorescente en disolución, que puede ser regulada según el isómero del clúster que se trate y, del sustituyente presente en el segundo Ccluster. Además, las propiedades fluorescentes son diferentes en disolución y en estado sólido. ➢Resultados y discusión II: preparación y estudio de sistemas d, The work presented in this thesis follows with two research lines initiated in the Catalysis and Inorganic Synthesis Group at Institute of Material Sciences of Barcelona (ICMAB-CSIC), based on the development of new boron cluster derivatives with photoluminescent properties and the preparation of high boron content systems. To move forward with these lines, the results and discussion section is divided in two parts: ➢ Results and discussion I: development and photophysical study of carboranes bearing fluorophores The first part consists of three chapters that describe the synthesis of ortho- and meta-carborane derivatives bonded to stilbene groups. The molecules prepared have been fully characterized using the common spectroscopic techniques and X-ray diffraction when possible. The new compounds have been studied from a photophysical point of view and the experimental results were completed with some theoretical calculations. Chapters 3 and 4 describe the synthetic routes to obtain stilbene-substituted with 1 or 2 boron cluster derivatives, following by the synthesis of carboranes-substituted with 2 stilbene units. The synthetic strategies have involved nucleophilic substitutions, electrophilic substitutions and Heck coupling reactions. The results obtained have shed light on the important role played by the nature of the carborane in the photophysical behavior of stilbene, not only in solution but in solid state. In Chapter 5 we decided to prepare larger molecules with an octavinyl-POSS core functionalized with eight carborane derivatives, through vinyl-stilbene groups. These compounds have shown a high thermal stability, as well as high fluorescence emission in solution, which can be tuned by the nature of carborane derivatives linked to the fluorescent moieties, as well as the substituent at the second Ccluster. Fluorescence properties of functionalized POSS in solid state have shown a different behavior to solutions. ➢ Results and discussion II: preparation and

An efficient process to produce boron cluster-graphene oxide nanohybrids that are highly dispersible in water and organic solvents is established for the first time. Dispersions of these nanohybrid materials in water were extraordinarily stable after one month. Characterization of hybrids after grafting of appropriate cobaltabisdicarbollide and closo-dodecaborate derivatives onto the surface of graphene oxide (GO) was done by FT-IR, XPS, and UV/Vis. Thermogravimetric analysis (TGA) clearly shows a higher thermal stability for the modified-GO nanohybrids compared to the parent GO. Of particular note, elemental mapping by energy-filtered transmission electron microscopy (EFTEM) reveals that a uniform decoration of the graphene oxide surface with the boron clusters is achieved under the reported conditions. Therefore, the resulting nanohybrid systems show exceptional physico-chemical and thermal properties, paving the way for an enhanced processability and further expanding the range of application for graphene-based materials.

Two novel styrene-containing meta-carborane derivatives substituted at the second carbon cluster atom (Cc) with either a methyl (Me), or a phenyl (Ph) group, are introduced herein alongside with a new set of stilbene-containing ortho- (o-) and meta- (m-) carborane dyads. The latter set of compounds has been prepared from styrenecontaining carborane derivatives via Heck coupling reaction. High regioselectivity has been achieved for these compounds by using a combination of palladium complexes [Pd2(dba)3]/[Pd(t-Bu3P)2] as a catalytic system, yielding exclusively E isomers. All compounds have been fully characterized and the crystal structures of seven of them analyzed by X-ray diffraction. The absorption spectra of these compounds are similar to those of their respective fluorophore groups (styrene or stilbene), showing very low influence of the substituent (Me or Ph) linked to the second Cc atom or the cluster isomer (o- or m-). On the other hand, fluorescence spectroscopy revealed high emission intensities for Me-o-carborane derivatives, whereas their Ph-o-carborane analogues evidenced an almost total lack of fluorescence, confirming the significant role of the substituent bound to the adjacent Cc in o-carboranes. In contrast, all the m-carborane derivatives display similar photoluminescence (PL) behavior regardless of the substituent attached to the second Cc, demonstrating its small influence on the emission properties. Additionally, m-carborane derivatives are significantly more fluorescent than their o- counterparts, reaching quantum yield values as high as 30.2%. Regarding the solid state emission, only stilbene-containing Ph-o-carborane derivatives, which showed very low fluorescence in solution, exhibited a notable PL emission in films attributed to the aggregation-induced emission. DFT calculations were performed to successfully complement the photoluminescence studies, supporting the experimentally observed photophysical behavior of the styrene and stilbene

Polyanionic and electroactive hybrids based on octasilsesquioxanes bearing metallacarborane units are developed. They show remarkable solubility in organic solvents and outstanding thermal stability. The metallacarboranes act as independent units simultaneously undergoing the reversible redox process.

A set of triads in which o- and m-carborane clusters are bonded to two stilbene units through Ccluster -CH2 bonds was synthesized, and their structures were confirmed by X-ray diffraction. A study on the influence of the o- and m- isomers on the absorption and photoluminescence properties of the stilbene units in solution revealed no charge-transfer contributions in the lowest excited state, as confirmed by (TD)DFT calculations. The presence of one or two B-I groups in m-carborane derivatives does not affect the emission properties of the stilbenes in solution, probably due to the rather large distance between the iodo substituents and the fluorophore. Nevertheless, a significant redshift of the photoluminescence (PL) emission maximum in the solid state (thin films and powder samples) compared to solution was observed; this can be traced back to PL sensitization, most probably due to more densely packed stilbene moieties. Remarkably, the PL absolute quantum yields of powder samples are significantly higher than those in solution, and this was attributed to the restricted environment and the aforementioned sensitization. Thus, the bonding of the carborane clusters to two stilbene units preserves their PL behavior in solution, but produces significant changes in the solid state. Furthermore, iodinated species can be considered to be promising precursors for theranostic agents in which both imaging and therapeutic functions could possibly be combined.

The synthesis and characterization of a set of poly(aryl ether) dendrimers with tetraphenylporphyrin as the core and 4, 8, 16, or 32 closo-carborane clusters are described. A regioselective hydrosilylation reaction on the allyl-terminated functions with carboranylsilanes in the presence of Karstedt's catalyst leads to different generations of boron-enriched dendrimers. This versatile approach allows the incorporation of a large number of boron atoms in the dendrimers' periphery. Translational diffusion coefficients (D) determined by DOSY NMR experiments permit estimation of the hydrodynamic radius (RH) and molecular size for each dendrimer. Furthermore, a notable correlation between D and the molecular weight (MW) is found and can be used to predict their overall size and folding properties. The UV-vis and emission behavior are not largely affected by the functionalization, therefore implying that the presence of carboranes does not alter their photoluminescence properties.