Artículos (Química Orgánica)
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Artículo Light-responsive glycosidase inhibitors: Tuning enzyme selectivity and switching factors through integrated chemical and optoglycomic strategies(Elsevier, 2025-07-15) Rivero Barbarroja, Gonzalo; Maisonneuve, Stéphane; Xie, Juan; García Fernández, José Manuel; Ortiz Mellet, Carmen; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). EspañaPhotopharmacology leverages light-responsive drugs to achieve spatiotemporal control over their activation and interactions with biological targets. This high level of precision is particularly crucial for therapeutic strategies that require sequential drug-target binding and dissociation, such as pharmacological chaperones (PCs) for lysosomal storage disorders (LSDs). PCs must tightly bind misfolded glycosidases in the endoplasmic reticulum (ER) to promote proper folding, yet efficiently dissociate in the lysosome to restore enzymatic function. Here, we demonstrate that azobenzene-equipped, photoswitchable sp2-iminosugars can fulfill these criteria by exploiting differential E-/Z-isomer interactions with aglycone-accommodating regions of target glycosidases. A diversity-oriented strategy was implemented, incorporating variations in glycomimetic portions, linkers, azobenzene substitution patterns, distal substituents, and valency to fine-tune light and temperature responsiveness. This approach yielded derivatives capable of selectively switching between α- and β-glucosidase inhibition, as well as conjugates exhibiting reversible nanomolar inhibition of human glucocerebrosidase, the dysfunctional enzyme in Gaucher disease, with remarkable switching factors under conditions that mirror the scenario at the ER and the lysosome. The results expand the scope of optoglycomics by providing a framework for designing photocommutators that enable reversible glycosidase modulation and laying the foundation for next-generation photoresponsive glycosidase inhibitors with therapeutic potential in LSDs and broader biomedical applications.Artículo Exploring a Novel Anti-Inflammatory Therapy for Diabetic Retinopathy Based on Glyco-Zeolitic-Imidazolate Frameworks(Multidisciplinary Digital Publishing Institute (MDPI), 2025-06-17) Díaz Paredes, Elena; Martín Loro, Francisco; Rodríguez Marín, Rocío; Gómez Jaramillo, Laura; Sánchez Fernández, Elena Matilde; Carrillo Carrión, Carolina; Arroba, Ana I.; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Instituto de Salud Carlos IIIDiabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp2-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response.Artículo Multimodal antiproliferative effects of oleanolic acid mitocans: In vitro and in vivo studies(Elsevier, 2025-04) Puerta, Adrián; González-Bakker, Aday; Romanos, Eduardo; Domínguez García, Inmaculada; Martínez Montiel, Mónica; Merino-Montiel, Penélope; Fernández-Bolaños Guzmán, José María; López López, Óscar; Padrón, José M.; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Union (UE); Junta de AndalucíaMitochondria-targeting drugs (mitocans) based on organic cations are emerging as powerful and selective cancer,therapeutics. In this study, we have evaluated a novel series of oleanolic acid-derived mitocans, revealing,nanomolar-range antiproliferative effects against human solid tumor cells. Continuous live-cell imaging revealed,extensive cytoplasmic vacuolation, while mechanistic studies identified paraptosis as the dominant form of cell,death. Remarkably, in vivo experiments demonstrated significant tumor growth inhibition in mice, with no,detectable toxicity at therapeutic doses. These findings highlight the potential of oleanolic acid-derived mitocans,as promising candidates for cancer therapy.Artículo β-Cyclodextrin-based geometrically frustrated amphiphiles as one-component, cell-specific and organ-specific nucleic acid delivery systems(Elsevier, 2025-01-01) Rivero Barbarroja, Gonzalo; López Fernández, José; Juárez Gonzálvez, Inmaculada; Fernández Clavero, C.; Di Giorgio, Christophe; Vélaz, Itziar; Ortiz Mellet, Carmen; García Fernández, José M.; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE)We introduce an innovative β-cyclodextrin (βCD)-prototype for delivering nucleic acids: “geometrically frustrated amphiphiles (GFAs).” GFAs are designed with cationic centers evenly distributed across the primary O6 and secondary O2 positions of the βCD scaffold, while hydrophobic tails are anchored at the seven O3 positions. Such distribution of functional elements differs from Janus-type architectures and enlarges the capacity for accessing strictly monodisperse variants. Changes at the molecular level can then be correlated with preferred self-assembly and plasmid DNA (pDNA) co-assembly behaviors. Specifically, GFAs undergo pH-dependent transition between bilayered to monolayered vesicles or individual molecules. GFA-pDNA nanocomplexes exhibit topological and internal order characteristics that are also a function of the GFA molecular architecture. Notably, adjusting the pKa of the cationic heads and the hydrophilic-hydrophobic balance, pupa-like arrangements implying axial alignments of GFA units flanked by quasi-parallel pDNA segments are preferred. In vitro cell transfection studies revealed remarkable differences in relative performances, which corresponded to distinct organ targeting outcomes in vivo. This allowed for preferential delivery to the liver and lung, kidney or spleen. The results collectively highlight cyclodextrin-based GFAs as a promising class of molecular vectors capable of finely tuning cell and organ transfection selectivityArtículo STD NMR Epitope Perturbation by Mutation Unveils the Mechanismof YM155 as an Arginine-Glycosyltransferases Inhibitor Effective inTreating Enteropathogenic Diseases(American Chemical Society, 2025-03) Ramírez Cárdenas, Jonathan; Taleb, Víctor; Calvaresi, Valeria; Struwe, WB; El Qaidi, Samir; Zhu, Congrui; Muñoz García, Juan Carlos; Angulo Álvarez, Jesús; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España; European Union (UE); Gobierno de AragónEnteropathogenic arginine-glycosyltransferases(Arg-GTs) alter higher eukaryotic proteins by attaching a GlcNAcresidue to arginine acceptor sites, disrupting essential pathwayssuch as NF-κB signaling, which promotes bacterial survival. Theseenzymes are potential drug targets for treating related diseases. Inthis study, we present a novel STD NMR Epitope Perturbation byMutation spectroscopic approach that, in combination withhydrogen−deuterium exchange mass spectrometry (HDX-MS),and molecular dynamics simulations, shows that the highly potentbroad-spectrum anticancer drug YM155 serves as a potentialnoncompetitive inhibitor of these enzymes. It induces aconformation of the arginine acceptor site unfavorable for GlcNActransfer, which underlies the molecular mechanism by which thiscompound exerts its inhibitory function. Finally, we also demonstrate that YM155 effectively treats enteropathogenic diseases in amouse model, highlighting its therapeutic potential. Overall, our data suggest that this compound can be repurposed to not only treatcancer but also infectious diseases.Artículo Light-controlled assembly and disassembly of cyclodextrin-bisazobenzene supramolecular complexes(Elsevier, 2025-04-16) Fernández Clavero, Carlos; Rivero Barbarroja, Gonzalo; Carmona, Thais; García Iriepa, C.; Marcelo, Gema; Tros de Ilarduya, Conchita; Ortiz Mellet, Carmen; García Fernández, José M.; Benito, Juan M.; Mendicuti, Francisco; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación. España; European Union (UE); Universidad de AlcaláThe inclusion complexation of a water soluble bis-azobenzene derivative (bis-Azo) and its monotopic analog (mono-Azo) with α-, β-, and γ-cyclodextrins (CyDs) was investigated as a prototype for light-responsive selfassembling systems. Using spectroscopic techniques (UV–vis, induced circular dichroism, 1 H NMR), computational methods (molecular mechanics and dynamics), and thermodynamic analyses, we examined the photoswitching properties, stability, and structural dynamics of these systems. The azobenzene moieties in the Eisomer of mono-Azo and bis-Azo consistently showed strong affinity for the αCyD cavity, characterized by high association constants. In contrast, no complex formation was observed upon photoinduced E-to-Z isomerization. For bis-Azo, this implies the formation of supramolecular αCyD dimers, with the spatial separation between the oppositely oriented host components determined by the connector linking the two azobenzene moieties in the Econfigured ditopic guest. This complex disassembles upon photoswitching, driven by the structural disruption associated with the Z-form. Both the E-and Z-isomers fitted in the cavity of βCyD, with moderate selectivity towards the E-form. A similar scenario was found for complexes with γCyD when using low concentrations of the host. Interestingly, at high concentrations γCyD formed low-solubility pseudopolyrotaxane-type supramolecular architectures with bis-Azo, which were disrupted upon Z-isomer photoisomerization. All the complexes demonstrated high fatigue resistance, maintaining structural integrity after multiple isomerization cycles. This work advances the design of stimuli-responsive preorganized supramolecular systems, with potential applications in nucleic acid delivery through dual pH/light-sensitive mechanisms.Artículo An isofagomine analogue with an amidine group inthe 1,6-position(Royal Society Open Science, 2024-02) Vaaland, I. Caroline; Christensen, Idd Andrea; Pejov, Ljupcho; Morén, Monika; Westlund, Nikolai; Santos Evangelista, Tereza C.; Sydnes, Magne O.; Aachmann, Finn L.; López López, Óscar; Lindbäck, Emil; Universidad de Sevilla. Departamento de Química Inorgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Agencia Estatal de Investigación. España; Junta de AndalucíaThe synthesis of an isofagomine analogue with an amidine group in the 1,6-position is described. Density functional theory calculations showed that this compound has a remarkably different charge distribution compared with isofagomine. This may explain why the amidine is a poor glycosidase inhibitor (IC50 > 50 µM against all tested enzymes) compared with isofagomine.Artículo Hydrogels and Nanogels: Pioneering the Future of Advanced Drug Delivery Systems(Multidisciplinary Digital Publishing Institute (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 Química Orgánica y Farmacéutica; Universidad de Sevilla. Departamento de Ingeniería y Ciencia de los Materiales y del Transporte; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). EspañaConventional 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.Artículo Exploring the Chemistry and Applications of Thio-, Seleno-, and Tellurosugars(Multidisciplinary Digital Publishing Institute (MDPI), 2025-05-05) Martínez Pascual, Roxana; Valera Zaragoza, Mario; Fernández-Bolaños Guzmán, José María; López López, Óscar; Universidad de Sevilla. Departamento de Química Orgánica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Junta de AndalucíaGiven the crucial roles of carbohydrates in energy supply, biochemical processes, signaling events and the pathogenesis of several diseases, the development of carbohydrate analogues, called glycomimetics, is a key research area in Glycobiology, Pharmacology, and Medicinal Chemistry. Among the many structural transformations explored, the replacement of endo- and exocyclic oxygen atoms by carbon (carbasugars) or heteroatoms, such as nitrogen (aza- and iminosugars), phosphorous (phosphasugars), sulfur (thiosugars), selenium (selenosugars) or tellurium (tellurosugars) have garnered significant attention. These isosteric substitutions can modulate the carbohydrate bioavailability, stability, and bioactivity, while introducing new properties, such as redox activity, interactions with pathological lectins and enzymes, or cytotoxic effects. In this manuscript we have focused on three major families of glycomimetics: thio-, seleno-, and tellurosugars. We provide a comprehensive review of the most relevant synthetic pathways leading to substitutions primarily at the endocyclic and glycosidic positions. The scope includes metal-catalyzed reactions, organocatalysis, electro- and photochemical transformations, free-radical processes, and automated syntheses. Additionally, mechanistic insights, stereoselectivity, and biological properties are also discussed. The structural diversity and promising bioactivities of these glycomimetics underscore their significance in this research area.Artículo 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.Artículo 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.Artículo 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.Artículo 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.Artículo 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.Artículo 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 AndalucíaA 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.Artículo 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 AndalucíaA 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.Artículo 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 AplicadaConventional 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.Artículo 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). EspañaChiral 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.Artículo 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 SevillaThe 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.Artículo 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.