Artículos (Química Orgánica)

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Fluorinated Man9 as a High Mannose Mimetic to Unravel Its Recognition by DC-SIGN Using NMR
(American Chemical Society, 2023-11-08) Silva Díaz, Adrián; Ramírez Cárdenas, Jonathan; Muñoz García, Juan Carlos; de la Fuente, M. Carmen; Thépaut, Michel; Fieschi, Franck; Ramos Soriano, Javier; Angulo Álvarez, Jesús; Rojo, Javier; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE)
Lectins are capable of reading out the structural information contained in carbohydrates through specific recognition processes. Determining the binding epitope of the sugar is fundamental to understanding this recognition event. Nuclear magnetic resonance (NMR) is a powerful tool to obtain this structural information in solution; however, when the sugar involved is a complex oligosaccharide, such as high mannose, the signal overlap found in the NMR spectra precludes an accurate analysis of the interaction. The introduction of tags into these complex oligosaccharides could overcome these problems and facilitate NMR studies. Here, we show the preparation of the Man9 of high mannose with some fluorine tags and the study of the interaction with its receptor, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). This fluorinated ligand has allowed us to apply heteronuclear two-dimensional (2D) 1H,19F STD-TOCSYreF NMR experiments, using the initial slope approach, which has facilitated the analysis of the Man9/DC-SIGN interaction, unequivocally providing the binding epitope.
Rational Design of Dual-Domain Binding Inhibitors for N-Acetylgalactosamine Transferase 2 with Improved Selectivity over the T1 and T3 Isoforms
(American Chemical Society, 2024-09-11) Compañón, Ismael; Ballard, Collin J.; Lira Navarrete, Enardi; Santos, Tanausú; Monaco, Serena; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Ghirardello, Mattía; Universidad de Sevilla. Departamento de Química Orgánica; Agencia Estatal de Investigación. España; Universidad de La Rioja; Gobierno de Aragón; European Union (UE)
The GalNAc-transferase (GalNAc-T) family, consisting of 20 isoenzymes, regulates the O-glycosylation process of mucin glycopeptides by transferring GalNAc units to serine/threonine residues. Dysregulation of specific GalNAc-Ts is associated with various diseases, making these enzymes attractive targets for drug development. The development of inhibitors is key to understanding the implications of GalNAc-Ts in human diseases. However, developing selective inhibitors for individual GalNAc-Ts represents a major challenge due to shared structural similarities among the isoenzymes and some degree of redundancy among the natural substrates. Herein, we report the development of a GalNAc-T2 inhibitor with higher potency compared to those of the T1 and T3 isoforms. The most promising candidate features bivalent GalNAc and thiophene moieties on a peptide chain, enabling binding to both the lectin and catalytic domains of the enzyme. The binding mode was confirmed by competitive saturation transfer difference NMR experiments and validated through molecular dynamics simulations. The inhibitor demonstrated an IC50 of 21.4 μM for GalNAc-T2, with 8- and 32-fold higher selectivity over the T3 and T1 isoforms, respectively, representing a significant step forward in the synthesis of specific GalNAc-T inhibitors tailored to the unique structural features of the targeted isoform.
Fluorinated trehalose analogues for cell surface engineering and imaging of Mycobacterium tuberculosis
(2024-08-12) Guy, Collette S.; Gott, James A.; Ramírez Cárdenas, Jonathan; de Wolf, Cristopher; Furze, Christopher M.; West, Geoff; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Fullam, Elizabeth; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE)
The sensitive, rapid and accurate diagnosis of Mycobacterium tuberculosis (Mtb) infection is a central challenge in controlling the global tuberculosis (TB) pandemic. Yet the detection of mycobacteria is often made difficult by the low sensitivity of current diagnostic tools, with over 3.6 million TB cases missed each year. To overcome these limitations there is an urgent need for next-generation TB diagnostic technologies. Here we report the use of a discrete panel of native 19F-trehalose (F-Tre) analogues to label and directly visualise Mtb by exploiting the uptake of fluorine-modified trehalose analogues via the mycobacterial trehalose LpqY-SugABC ATP-binding cassette (ABC) importer. We discovered the extent of modified F-Tre uptake correlates with LpqY substrate recognition and characterisation of the interacting sites by saturation transfer difference NMR coupled with molecular dynamics provides a unique glimpse into the molecular basis of fluorine-modified trehalose import in Mtb. Lipid profiling demonstrated that F-Tre analogues modified at positions 2, 3 and 6 are incorporated into mycobacterial cell-surface trehalose-containing glycolipids. This rapid one-step labelling approach facilitates the direct visualisation of F-Tre-labelled Mtb by Focused Ion Beam (FIB) Secondary Ion Mass Spectrometry (SIMS), enabling detection of the Mtb pathogen. Collectively, our findings highlight that F-Tre analogues have potential as tools to probe and unravel Mtb biology and can be exploited to detect and image TB.
Fast Quantitative Validation of 3D Models of Low-Affinity Protein-Ligand Complexes by STD NMR Spectroscopy
(American Chemical Society, 2024-06-07) Nepravishta, Ridvan; Ramírez Cárdenas, Jonathan; Rocha, Gabriel; Walpole, Samuel; Hicks, Thomas; Monaco, Serena; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Universidad de Sevilla. Departamento de Química Orgánica; Biotechnology and Biological Sciences Research Council (BBSRC). U. K.; Agencia Estatal de Investigación. España; Ministerio de Ciencia e Innovación (MICIN). España; European Union (UE)
Low-affinity protein–ligand interactions are important for many biological processes, including cell communication, signal transduction, and immune responses. Structural characterization of these complexes is also critical for the development of new drugs through fragment-based drug discovery (FBDD), but it is challenging due to the low affinity of fragments for the binding site. Saturation transfer difference (STD) NMR spectroscopy has revolutionized the study of low-affinity receptor–ligand interactions enabling binding detection and structural characterization. Comparison of relaxation and exchange matrix calculations with 1H STD NMR experimental data is essential for the validation of 3D structures of protein–ligand complexes. In this work, we present a new approach based on the calculation of a reduced relaxation matrix, in combination with funnel metadynamics MD simulations, that allows a very fast generation of experimentally STD-NMR-validated 3D structures of low-affinity protein–ligand complexes.
Differential Solvent DEEP-STD NMR and MD Simulations Enable the Determinants of the Molecular Recognition of Heparin Oligosaccharides by Antithrombin to Be Disentangled
(MDPI, 2024-04-26) Parafioriti, Michela; Elli, Stefano; Muñoz García, Juan Carlos; Ramírez Cárdenas, Jonathan; Yates, Edwin A.; Angulo Álvarez, Jesús; Guerrini, Marco; Universidad de Sevilla. Departamento de Química Orgánica; Fundación G. Ronzoni. Italia; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
The interaction of heparin with antithrombin (AT) involves a specific sequence corresponding to the pentasaccharide GlcNAc/NS6S-GlcA-GlcNS3S6S-IdoA2S-GlcNS6S (AGA*IA). Recent studies have revealed that two AGA*IA-containing hexasaccharides, which differ in the sulfation degree of the iduronic acid unit, exhibit similar binding to AT, albeit with different affinities. However, the lack of experimental data concerning the molecular contacts between these ligands and the amino acids within the protein-binding site prevents a detailed description of the complexes. Differential epitope mapping (DEEP)-STD NMR, in combination with MD simulations, enables the experimental observation and comparison of two heparin pentasaccharides interacting with AT, revealing slightly different bound orientations and distinct affinities of both glycans for AT. We demonstrate the effectiveness of the differential solvent DEEP-STD NMR approach in determining the presence of polar residues in the recognition sites of glycosaminoglycan-binding proteins.
Organocatalytic Applications of Sulfonyl Squaramides in Anion-Recognition Strategies
(Willey, 2024-10-16) Benítez Narváez, Manuel; Matador Martínez, Esteban; Velázquez Muñoz, Marta; Lassaletta, José M.; Fernández Fernández, Rosario Fátima; Monge Fernández, David; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
A modular, 3-steps protocol for the synthesis of N-sulfonyl squaramides has been developed. The strategic installation of a tetrahedral, electron-withdrawing sulfonyl group into the squaramido core allowed the prevention of undesired self-aggregations, therefore upgrading the solubility in common organic solvents, and moreover, enhancing their H-bond donor abilities for molecular recognition. These unique features have been efficiently exploited in two different ion-pairing reactions: (i) the challenging C4-selective dearomatization of 2-picoline with silyl ketene acetals and (ii) the tritylation of N-methylindole. Furthermore, their catalytic activities have been directly compared with other common and well-established (thio)urea analogues and related H-bond donors, revealing that highly acidic designs are essential to reach optimal catalytic performances.
Axially Chiral N-Oxide Catalysts for the Allylation and Crotylation of Aromatic Aldehydes: Exploiting Nonlinear Effects
(Willey, 2024-07-09) Romero Arenas, Antonio; Ramírez López, Pedro; Iglesias Sigüenza, Francisco Javier; Fernández Fernández, Rosario Fátima; Ros Lao, Abel; Lassaletta, José M.; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
A new family of IAN-type amine N-oxides is presented as catalysts for the allylation and crotylation of aromatic aldehydes with allyltrichlorosilanes. These reaction exhibit a remarkably positive nonlinear effect which enables utilization of the catalysts in subenantiopure form. As enantiopure catalysts are not required under this regime, the synthesis of these N-oxides is straightforward through catalytic asymmetric synthesis, avoiding lenghty synthesis from the chiral pool or resolution of diastereoisomers. Studies of the corresponding crotylation with Z- and E-crotylsilanes suggest that the reaction proceeds through a chair-like transition state.
Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems
(MDPI, 2025-02-07) Delgado-Pujol, Ernesto J.; Martínez Muñoz, Guillermo; Casado Jurado, David; Vázquez Cabello, Juan; León-Barberena, Jesús; Rodríguez Lucena, David; Torres Hernández, Yadir; Alcudia Cruz, Ana; Begines Ruiz, Belén; Universidad de Sevilla. Departamento de Ingeniería y Ciencia de los Materiales y del Transporte; Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Universidad de Sevilla. TEP123: Metalurgia e Ingeniería de los Materiales; Universidad de Sevilla. FQM408: Química Farmacéutica Aplicada
Conventional drug delivery approaches, including tablets and capsules, often suffer from reduced therapeutic effectiveness, largely attributed to inadequate bioavailability and difficulties in ensuring patient adherence. These challenges have driven the development of advanced drug delivery systems (DDS), with hydrogels and especially nanogels emerging as promising materials to overcome these limitations. Hydrogels, with their biocompatibility, high water content, and stimuli-responsive properties, provide controlled and targeted drug release. This review explores the evolution, properties, and classifications of hydrogels versus nanogels and their applications in drug delivery, detailing synthesis methods, including chemical crosslinking, physical self-assembly, and advanced techniques such as microfluidics and 3D printing. It also examines drug-loading mechanisms (e.g., physical encapsulation and electrostatic interactions) and release strategies (e.g., diffusion, stimuli-responsive, and enzyme-triggered). These gels demonstrate significant advantages in addressing the limitations of traditional DDS, offering improved drug stability, sustained release, and high specificity. Their adaptability extends to various routes of administration, including topical, oral, and injectable forms, while emerging nanogels further enhance therapeutic targeting through nanoscale precision and stimuli responsiveness. Although hydrogels and nanogels have transformative potential in personalized medicine, challenges remain in scalable manufacturing, regulatory approval, and targeted delivery. Future strategies include integrating biosensors for real-time monitoring, developing dual-stimuli-responsive systems, and optimizing surface functionalization for specificity. These advancements aim to establish hydrogels and nanogels as cornerstones of next-generation therapeutic solutions, revolutionizing drug delivery, and paving the way for innovative, patient-centered treatments.
Dual Luminescence and Infrared Circularly Polarized Luminescence up to 900 nm with Platinum Complexes Bearing a Helical Donor-acceptor Ligand
(Royal Society of Chemistry, 2024) Vázquez Domínguez, Pablo; Horojat, M.; Suits, E.; Fernández de Córdova, Francisco José; Vanthuyne, N.; Ros Lao, Abel; Vanthuyne, Nicolas; Jacquemin, Denis; Universidad de Sevilla. Departamento de Química Orgánica; European Union (UE); Consejo Superior de Investigaciones Científicas (CSIC); Ministerio de Ciencia e Innovación (MICIN). España
Chiral molecular materials able to emit circularly polarized luminescence (CPL) have attracted considerable interest in the last few decades, due to the potential of CP-light in a wide range of applications. While CP luminescent molecules with blue, green, and yellow emissions are now well-reported, NIR CPL from organic and organometallic compounds lags behind due to the dual challenge of promoting radiative deexcitation of the excited state in this low energy region while assuring a significant magnetic dipole transition moment, a prerequisite for generating CPL. Based on a versatile axially chiral arylisoquinoline ligand, we report the synthesis and chiroptical properties of chiral donor-acceptor platinum(ii) complexes displaying CPL that extends up to almost 900 nm. Interestingly, these emitters show both fluorescence and phosphorescence emissions in solution, with intensities depending on the charge-transfer character of the organic ligand. Experimental and theoretical investigations show that this feature strongly impacts the intersystem crossing event between the singlet and triplet excited states of these complexes and the related phosphorescence lifetime. The effect is less important regarding the CPL, and most complexes show luminescence dissymmetry factors with values up to ca. 2 × 10−3 around 800 nm.
Multifaceted Sulfonamide-Derived Thiosemicarbazones: Combining Metal Chelation and Carbonic Anhydrases Inhibition in Anticancer Therapy
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-01-30) Martínez Montiel, Mónica; Arrighi, Giulia; Begines Aguilar, Paloma; González-Bakker, Aday; Puerta, Adrián; Fernandes, Miguel X.; Merino-Montiel, Penélope; Montiel-Smith, Sara; Nocentini, Alessio; Supuran, Claudiu T.; Padrón, José M.; Fernández-Bolaños Guzmán, José María; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Universidad de Sevilla
The selective inhibition of key enzymes, such as carbonic anhydrases (CAs IX and XII), which are overexpressed in cancer tissues, has emerged as a promising strategy in cancer research. However, a multitarget approach is often preferred to achieve enhanced therapeutic outcomes. In this study, aryl sulfonamides were conjugated with a thiosemicarbazone moiety to enable dual functionality: the inhibition of CAs and the chelation of metal cations. Several structural factors were systematically modified, including the position of the sulfonamido group, the length of the linker, the nature of the aromatic residue, and the type of substituents. Tumor-associated CAs IX and XII inhibition was evaluated using the stopped-flow CO2 hydrase assay, and the inhibition constants (Ki) were determined. The most promising compounds were further analyzed through molecular docking simulations. Metal chelation capabilities were evaluated using UV–Vis spectroscopy, while antiproliferative activities were measured using the sulforhodamine B (SBR) assay. Additionally, holotomographic 3D microscopy was employed to investigate the mechanisms of cell death. Sulfonamido-derived Schiff bases were synthesized through a three-step procedure that did not require column chromatography purification: (1) isothiocyanation of amino-sulfonamides, (2) nucleophilic addition of hydrazine, and (3) acid-promoted condensation with different aldehydes (benzaldehydes or pyridine-2-carboxaldehyde). The synthesized compounds exhibited inhibition of CAs in the low nanomolar to submicromolar range, with selectivity largely influenced by structural features. Notably, the m-sulfonamide derivative 5b, bearing a pyridin-2-yl residue, demonstrated potent and selective inhibition of CA IX (Ki = 4.9 nM) and XII (Ki = 5.6 nM). Additionally, it efficiently chelated Fe2+, Fe3+, and Cu2+ and showed promising antiproliferative activity (GI50 4.5–10 µM). Mechanistic studies revealed that apoptosis was involved in its mode of action. Therefore, the synergistic integration of sulfonamides and thiosemicarbazones represents an effective strategy for the development of multimodal anticancer agents.
Effects of Sesquiterpene Lactones on Primary Cilia Formation (Ciliogenesis)
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-10-23) Murillo Pineda, Marina; Coto Cid, Juan Manuel; Romero, María; Zorrilla, Jesús G.; Chinchilla, Nuria; Medina Calzada, Zahara; Varela, Rosa M.; Juárez Soto, Álvaro; Macías, Francisco A.; Reales, Elena; Universidad de Sevilla. Departamento de Química orgánica; European Union (UE)
Sesquiterpene lactones (SLs), plant-derived metabolites with broad spectra of biological effects, including anti-tumor and anti-inflammatory, hold promise for drug development. Primary cilia, organelles extending from cell surfaces, are crucial for sensing and transducing extracellular signals essential for cell differentiation and proliferation. Their life cycle is linked to the cell cycle, as cilia assemble in non-dividing cells of G0/G1 phases and disassemble before entering mitosis. Abnormalities in both primary cilia (non-motile cilia) and motile cilia structure or function are associated with developmental disorders (ciliopathies), heart disease, and cancer. However, the impact of SLs on primary cilia remains unknown. This study evaluated the effects of selected SLs (grosheimin, costunolide, and three cyclocostunolides) on primary cilia biogenesis and stability in human retinal pigment epithelial (RPE) cells. Confocal fluorescence microscopy was employed to analyze the effects on primary cilia formation (ciliogenesis), primary cilia length, and stability. The effects on cell proliferation were evaluated by flow cytometry. All SLs disrupted primary cilia formation in the early stages of ciliogenesis, irrespective of starvation conditions or cytochalasin-D treatment, with no effect on cilia length or cell cycle progression. Interestingly, grosheimin stabilized and promoted primary cilia formation under cilia homeostasis and elongation treatment conditions. Thus, SLs have potential as novel drugs for ciliopathies and tumor treatment.
Engineering nanoscale glyco-zeolitic-imidazolate frameworks: Insights into the mechanism of formation
(Elsevier, 2025-03) Rodríguez Marín, Rocío; Rodríguez Gómez, Salvador; Hamad, Said; Sánchez Fernández, Elena Matilde; Carrillo Carrión, Carolina; Universidad de Sevilla. Departamento de Química orgánica; Universidad de Sevilla. Departamento de Física Atómica, Molecular y Nuclear; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla
The efficient encapsulation of large carbohydrates into porous metal-organic frameworks (MOFs), and not simply attached to the MOF's surface, is still challenging and underexplored. In this work we have investigated the scope of an optimized synthetic procedure following a biomimetic mineralization strategy for the encapsulation of a variety of therapeutic glycolipids within a Zeolitic-Imidazolate Framework-8 nanostructure (GlycoZIFs). In all cases, regardless of the glycosidic linkage nature of the glycolipid, we obtained uniform, crystalline and reproducible GlycoZIFs nanoparticles by using the same optimized experimental conditions, which demonstrate the versatility of our approach. Our experimental data revealed that the formation of glyco-micelles, by taking advantage of the surfactant-like character of these glycolipids, is key to promote the nucleation of ZIF-8 around, allowing thus a precise control of the spatial location and amount of glycodrug encapsulated in each ZIF-particle. In turn, the electronic structure calculations showed that there is a strong interaction between the hydroxyl groups in positions C3 and C4 of the glycone core of the glycolipid and the Zn atoms on the ZIF-8 surface, suggesting that those favourable glyco-ZIF interactions also played an important role to induce the ZIF-8 nucleation. Experimental control data and computational studies obtained with a protected glycolipid featuring O-acetyl groups supported that conclusion.
Oleuropein down-regulated IL-1β-induced inflammation and oxidative stress in human synovial fibroblast cell line SW982
(Royal Society of Chemistry, 2017-05) Castejón Martínez, María Luisa; Rosillo Ramírez, María de los Ángeles; Montoya García, Tatiana; González Benjumea, Alejandro; Fernández-Bolaños Guzmán, José María; Alarcón de la Lastra Romero, Catalina; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Química orgánica
Rheumatoid arthritis (RA) is a chronic and systemic inflammatory autoimmune disease mainly characterized by aggressive hyperproliferation of synovial fibroblasts (SFs). It is accompained by a massive infiltration of inflammatory immune cells inducing progressive matrix degradation, destruction of cartilage and bone erosion through the production of inflammatory mediators. Oleuropein is the most prevalent phenolic component in olive leaves, seed, pulp and peel of unripe olives and is responsible for the characteristic bitter taste of unprocessed olives. This secoiridoid possesses well-documented pharmacological properties, including antioxidant and anti-inflammatory properties, and is available as a food supplement in Mediterranean countries. However, to date, anti-arthritic effects of oleuropein on SFs have not been yet elucidated. Thus, the aim of the present study was to investigate the potential effects of oleuropein, on IL-1β-induced production of inflammatory mediators and oxidative stress in the human synovial sarcoma cell line (SW982). In order to gain a better insight into mechanisms of action, signaling pathways were also explored. Cell viability was determined using the sulforhodamine B (SRB) assay. The expression of inflammatory cytokines IL-6, TNF-α, MMP-1 and MMP-3 was evaluated by ELISA. Moreover, changes in the protein expression of cyclooxygenase (COX)-2, microsomal prostaglandin E synthase-1 (mPGES-1) as well as mitogen-activated protein kinase (MAPKs), nuclear factor kappa B (NF-κB), and nuclear factor-erythroid 2-related and heme oxygenase-1 (HO-1) signalling pathways were analysed by western blot. Oleuropein exerted anti-inflammatory and anti-oxidant effects via down-regulation of MAPK and NF-κB signaling pathways and induction of Nrf2-linked HO-1 controlling the production of inflammatory mediators decreasing IL-6 and TNF-α cytokines, MMP-1 and MMP-3 levels and mPGES-1 and COX-2 overexpression. Thus, oleuropein might provide a basis for developing a new dietary strategy for the prevention and management of RA.
Anti-inflammatory and joint protective effects of extra-virgin olive-oil polyphenol extract in experimental arthritis
(Elsevier, 2014-12) Rosillo Ramírez, María de los Ángeles; Alcaraz, María José; Sánchez Hidalgo, Marina; Fernández-Bolaños Guzmán, José María; Alarcón de la Lastra Romero, Catalina; Ferrándiz, María Luisa; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Química orgánica
The consumption of extra virgin olive oil (EVOO) in Mediterranean countries has shown beneficial effects. A wide range of evidence indicates that phenolic compounds present in EVOO are endowed with anti-inflammatory properties. In this work, we evaluated the effects of EVOO-polyphenol extract (PE) in a model of rheumatoid arthritis, the collagen-induced arthritis model in mice. On day 0, DBA-1/J mice were immunized with bovine type II collagen. On day 21, mice received a booster injection. PE (100 and 200 mg/kg) was orally administered once a day from days 29 to 41 to arthritic mice. We have demonstrated that PE decreases joint edema, cell migration, cartilage degradation and bone erosion. PE significantly reduced the levels of proinflammatory cytokines and prostaglandin E2 in the joint as well as the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1. Our data indicate that PE inhibits c-Jun N-terminal kinase, p38 and signal transducer and activator of transcription-3. In addition, PE decreases nuclear factor κB translocation leading to the down-regulation of the arthritic process. These results support the interest of natural diet components in the development of therapeutic products for arthritic conditions.
Preventive effects of dietary hydroxytyrosol acetate, an extra virgin olive oil polyphenol in murine collagen-induced arthritis
(Wiley, 2015-09-18) Rosillo Ramírez, María de los Ángeles; Sánchez Hidalgo, Marina; González Benjumea, Alejandro; Fernández-Bolaños Guzmán, José María; Lubberts, Erik; Alarcón de la Lastra Romero, Catalina; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Química orgánica
Hydroxytyrosol acetate (HTy-Ac), an extra virgin olive oil (EVOO) polyphenol, has recently exhibited antioxidant and anti-inflammatory effects on LPS-stimulated macrophages and ulcerative colitis. This study was designed to evaluate dietary HTy-Ac supplementation effects on collagen-induced arthritis (CIA) in mice. Methods and results: DBA-1/J mice were fed from weaning with 0.05% HTy-Ac. After 6 weeks, arthritis was induced by type II collagen. Mice were sacrificed 42 days after first immunization. Blood was recollected and paws were histological and biochemically processed. HTy-Ac diet significantly prevented arthritis development and decreased serum IgG1 and IgG2a, cartilage olimeric matrix protein (COMP) and metalloproteinase-3 (MMP-3) levels, as well as, pro-inflammatory cytokines levels (TNF-α, IFN-γ, IL-1β, IL-6 and IL-17A). The activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinases (MAPKs) and nuclear transcription factor-kappa B (NF-κB) pathways were drastically ameliorated whereas nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions were significantly up-regulated in those mice fed with HTy-Ac. Conclusion: HTy-Ac improved the oxidative events and returned pro-inflammatory proteins expression to basal levels probably through JAK/STAT, MAPKs and NF-κB pathways. HTy-Ac supplement might provide a basis for developing a new dietary strategy for the prevention of rheumatoid arthritis.
Tuning of β-glucosidase and α-galactosidase inhibition by generation and in situ screening of a library of pyrrolidine-triazole hybrid molecules
(Elsevier, 2017-09-29) Martínez Bailén, Macarena; Carmona, Ana T.; Moreno Clavijo, Elena; Robina, Inmaculada; Ide, Daisuke; Kato, Atsushi; Moreno Vargas, Antonio José; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía; Universidad de Sevilla. FQM345: Química de Biomoléculas y Análogos.
The preliminary screening of two libraries of epimeric (pyrrolidin-2-yl)triazoles (14a-s and 22a-s), generated via click chemistry, allowed the rapid identification of four α-galactosidase (coffee beans) inhibitors (22b,k,p,r) and two β-glucosidase (almond) inhibitors (14b,f) in the low μM range. The additional biological analysis of 14b,f towards β-glucocerebrosidase (human lysosomal β-glucosidase), as target enzyme for Gaucher disease, showed a good correlation with the inhibition results obtained for the plant (almond) enzyme. Surprisingly, although these compounds showed inhibition towards β-glucocerebrosidase as acid hydrolase, they did not inhibit bovine liver β-glucosidase as neutral hydrolase. In contrast to what was observed for β-glucosidase inhibition, the coffee beans α-galactosidase inhibitors of the epimeric library (22b,k,p,r) only showed weak inhibition towards human lysosomal α-galactosidase.
Clase invertida síncrona en asignaturas STEM
(Ministry Education and Science, 2021-03) Maya Díaz, Celia María; Iglesias Sigüenza, Francisco Javier; Giménez Font, Xavier; Universidad de Sevilla. Departamento de Química Inorgánica; Universidad de Sevilla. Departamento de Química orgánica
Se presenta una metodología de clase invertida, con modificaciones sincrónicas para adaptarse a la dificultad propia de las materias STEM. La clase Invertida Síncrona refuerza la tutoría inicial, para resolver las dudas de los alumnos que les impiden progresar a través del material que trabajan fuera del aula. A continuación, una dinámica de trabajo en grupo, aprendizaje basado en problemas, cuestionarios de integración, y evaluación formativa por pares, dan lugar a una destacable mejora de los resultados académicos, junto a una reducción del tiempo de trabajo y un incremento significativo en el grado de satisfacción del alumnado. Se discute su aplicación a tres asignaturas del Grado en Química de la Universidad de Sevilla, así como una asignatura del Grado de Química de la Universidad de Barcelona.
Atroposelective Transfer Hydrogenation of Biaryl Aminals via Dynamic Kinetic Resolution. Synthesis of Axially Chiral Diamines
(American Chemical Society, 2021-03-18) Carmona, José A.; Rodríguez Franco, Carlos; López Serrano, Joaquín; Ros Lao, Abel; Iglesias Sigüenza, Francisco Javier; Fernández Fernández, Rosario; Lassaletta, José M.; Hornillos, Valentín; Universidad de Sevilla. Departamento de Química Inorgánica; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
An efficient dynamic kinetic resolution (DKR) approach for the synthesis of axially chiral diamines has been developed on the basis of a ruthenium-catalyzed enantioselective transfer hydrogenation. The strategy relies on the configurational instability of cyclic biaryl aminal precursors in equilibrium with their amino-imine open forms, as supported by DFT calculations. This protocol features a broad substrate scope of aliphatic amines and biaryl scaffolds and proceeds under very mild conditions, allowing the preparation of BINAM homologues in good to high yields and nearly perfect enantioselectivities (up to 99% ee).
Asymmetric cross-aldol reactions of α-keto hydrazones and α,β-unsaturated γ-keto hydrazones with trifluoromethyl ketones
(Royal Society of Chemistry, 2021-11-18) Alberca Manzano, Saúl; Matador Martínez, Esteban; Iglesias Sigüenza, Francisco Javier; Retamosa Hernández, María Gracia; Fernández Fernández, Rosario Fátima; Lassaletta, José M.; Monge Fernández, David; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Junta de Andalucía
α-Keto hydrazones and α,β-unsaturated γ-keto hydrazones are suitable pro-nucleophiles for asymmetric cross-aldol reactions with trifluoromethyl ketones via aza-di(tri)enamine-type intermediates. A quinidine-derived primary amine catalyst affords tertiary trifluoromethylated alcohols in good-to-excellent yields and high enantioselectivities. Subsequent transformations of hydrazono moieties yield appealing fluorinated carboxylic acids, 1,4-dicarbonyls and γ-keto acids.
Asymmetric Sulfoxidations Catalyzed by Bacterial Flavin-Containing Monooxygenases
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-07-25) Gonzalo Calvo, Gonzalo de; Coto Cid, Juan Manuel; Lončar, Nikola; Fraaije, Marco W.; Universidad de Sevilla. Departamento de Química orgánica
Flavin-containing monooxygenase from Methylophaga sp. (mFMO) was previously discovered to be a valuable biocatalyst used to convert small amines, such as trimethylamine, and various indoles. As FMOs are also known to act on sulfides, we explored mFMO and some mutants thereof for their ability to convert prochiral aromatic sulfides. We included a newly identified thermostable FMO obtained from the bacterium Nitrincola lacisaponensis (NiFMO). The FMOs were found to be active with most tested sulfides, forming chiral sulfoxides with moderate-to-high enantioselectivity. Each enzyme variant exhibited a different enantioselective behavior. This shows that small changes in the substrate binding pocket of mFMO influence selectivity, representing a tunable biocatalyst for enantioselective sulfoxidations.

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