Artículos (Química Orgánica)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10924

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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.
Lewis Acid-Base Interactions as a Racemization Strategy for the Atroposelective Synthesis of (Hetero)biaryls via Dynamic Kinetic Resolution
(John Wiley & Sons, 2024-07-08) Carmona, José A.; Rodríguez-Franco, Carlos; Fernández Fernández, Rosario Fátima; Lassaletta, José M.; Hornillos, Valentín; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Junta de Andalucía
Due to their molecular topology, atropisomers serve as highly valuable chiral frameworks for diverse applications across academic research and industry. Despite the availability of numerous established catalytic methods for their synthesis, there is still a high demand for the development of novel and resourceful strategies. In this concept article, we will detail our studies on the use of transient Lewis acid-base interactions (LABI) as a dynamization strategy for the synthesis of (hetero)biaryl atropisomers by Dynamic Kinetic Resolution (DKR). The formation of cyclic transition states, resulting from the interaction between an acidic functionality and a basic counterpart, plays a key role in facilitating racemization by substantially reducing the barrier to atropisomerization. In this scenario, we have employed transformations aimed at neutralizing the acidic nature of the Lewis acid, ultimately leading to the formation of configurationally stable enantioenriched compounds. The design of substrates and the employment of stereoselective strategies based on transition metal and biocatalysis for their resolution is detailed. Specific emphasis on the preparation of axially chiral motifs commonly found in catalysis or medicinal chemistry will also be given.
Hydrogen-Bonding Activation of Gold(I) Chloride Complexes: Enantioselective Synthesis of 3(2H)-Furanones by a Cycloisomerization-Addition Cascade
(American Chemical Society, 2024-07-11) Elías-Rodríguez, Pilar; Benítez Narváez, Manuel; Iglesias Sigüenza, Francisco Javier; Díez Martín, Elena; 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
Enantioselective synthesis of 3(2H)-furanones has been achieved using the intermolecular H-bonding activation of gold(I) chloride complexes. A DM-BINAP [(R)-(+)-2,2′-Bis[di(3,5-xylyl)phoshino]-1,1′-binaphthyl] digold(I) dichloride complex in combination with a sulfonyl squaramide (SO2Sq) has been identified as the optimal catalytic system. The process involves a 5-endo-dig oxa-cyclization followed by stereocontrolled addition of indoles. Interestingly, the soft L*Au-Cl activation by H-bonding allowed the recovery of both L*Au-Cl and the activator after chromatographic purification.
Enantioselective synthesis of α-aryl α-hydrazino phosphonates
(Royal Society of Chemistry, 2024-05-23) Alberca, Saúl; Romero-Parra, Javier; Fernández López, Israel; Fernández Fernández, Rosario Fátima; Lassaletta, José María; Monge Fernández, David; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; Junta de Andalucía
Catalysts generated in situ by the combination of pyridine-hydrazone N,N-ligands and Pd(TFA)2 have been applied to the addition of arylboronic acids to formylphosphonate-derived hydrazones, yielding α-aryl α-hydrazino phosphonates in excellent enantioselectivities (96 → 99% ee). Subsequent removal of the benzyloxycarbonyl (Cbz) N-protecting group afforded key building blocks en route to appealing artificial peptides, herbicides and antitumoral derivatives. Experimental and computational data support a stereochemical model based on aryl-palladium intermediates in which the phosphono hydrazone coordinates in its Z-configuration, maximizing the interactions between the substrate and the pyridine-hydrazone ligand.
Assessing the Potential of 1,2,3-Triazole-Dihydropyrimidinone Hybrids Against Cholinesterases: In Silico, In Vitro, and In Vivo Studies
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-10-17) Gastalho, Carlos M.; Sena, Ana M.; López López, Óscar; Fernández-Bolaños Guzmán, José María; García-Sosa, Alfonso T.; Pereira, Florbela; Antunes, Célia M.; Costa, Ana R.; Burke, Anthony J.; Carreiro, Elisabete P.; Universidad de Sevilla. Departamento de Química orgánica; Fundação para a Ciência e a Tecnologia (FCT); Estonian Research Council; Ministerio de Ciencia e Innovación (MICIN). España
Combining the pharmacological properties of the 1,2,3-triazole and dihydropyrimidinone classes of compounds, two small families of mono- and di(1,2,3-triazole)-dihydropyrimidinone hybrids, A and B, were previously synthesized. The main objective of this work was to investigate the potential anti-Alzheimer effects of these hybrids. The inhibitory activities of cholinesterases (AChE and BuChE), antioxidant activity, and the inhibitory mechanism through in silico (molecular docking) and in solution (STD-NMR) experiments were evaluated. The 1,2,3-triazole-dihydropyrimidinone hybrids (A and B) showed moderate in vitro inhibitory activity on eqBuChE (IC50 values between 1 and 58.4 μM). The best inhibitor was the hybrid B4, featuring two 1,2,3-triazole cores, which exhibited stronger inhibition than galantamine, with an IC50 of 1 ± 0.1 μM for eqBuChE, through a mixed inhibition mechanism. Among the hybrids A, the most promising inhibitor was A1, exhibiting an IC50 of 12 ± 2 µM, similar to that of galantamine. Molecular docking and STD-NMR experiments revealed the key binding interactions of these promising inhibitors with BuChE. Hybrids A and B did not display Artemia salina toxicity below 100 μM.
Biocompatible metal-organic frameworks as promising platforms to eradicate HIV reservoirs ex vivo in people living with HIV
(Royal Society of Chemistry, 2024-04-17) Lebrón Romero, José Antonio; Ostos Marcos, Francisco José; Martínez-Santa, Marta; García-Moscoso, Francisco; López-López, Manuel; Moyá Morán, María Luisa; Bernal Pérez, Eva; Bachiller, Sara; González-Ulloa, Gabriel; Rodríguez Lucena, David; Lopes-Costa, Tania; Fernández Torres, Rut; Ruiz-Mateos, Ezequiel; Pedrosa, José María; Rafii-El-Idrissi Benhnia, Mohammed; López-Cornejo, María del Pilar; Universidad de Sevilla. Departamento de Química Analítica; Universidad de Sevilla. Departamento de Química Física; Universidad de Sevilla. Departamento de Química orgánica; Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología; Junta de Andalucía; Universidad de Sevilla; Ministerio de Ciencia e Innovación (MICIN). España
The HIV attacks the immune system provoking an infection that is considered a global health challenge. Despite antiretroviral treatments being effective in reducing the plasma viral load in the blood to undetectable levels in people living with HIV (PLWH), the disease is not cured and has become chronic. This happens because of the existence of anatomical and cellular viral reservoirs, mainly located in the lymph nodes and gastrointestinal tract, which are composed of infected CD4+ T cells with a resting memory phenotype and inaccessible to antiretroviral therapy. Herein, a new therapeutic strategy based on nanotechnology is presented. Different combinations of antiretroviral drugs (bictegravir/tenofovir/emtricitabine and nevirapine/tenofovir/emtricitabine) and toll-like receptor agonists were encapsulated into metal-organic frameworks (MOFs) PCN-224 and ZIF-8. The encapsulation efficiencies of all the drugs, as well as their release rate from the carriers, were measured. In vitro studies about the cell viability, the hemocompatibility, and the platelet aggregation of the MOFs were carried out. Epifluorescence microscopy assays confirmed the ability of ZIF-8 to target a carboxyfluorescein probe inside HeLa cell lines and PBMCs. These results pave the way for the use of these structures to eliminate latent HIV reservoirs from anatomical compartments through the activation of innate immune cells, and a higher efficacy of the triplet combinations of antiretroviral drugs.
Studies on the Regioselective Rearrangement of Azanorbornanic Aminyl Radicals into 2,8-Diazabicyclo[3.2.1]oct-2-ene Systems
(American Chemical Society, 2022) Gil de Montes Rojas, Enrique; Tallarida, Matteo A.; Carmona Asenjo, Ana Teresa; Navo, Claudio D.; Robina Ramírez, Inmaculada; Elías Rodríguez, María del Pilar; Jiménez Oses, Gonzalo; Moreno Vargas, Antonio José; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C–N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (Bu3SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.2.1]azabicyclic) aminyl radicals into 2,8-diazabicyclo[3.2.1]oct-2-ene systems. With the aim to establish the structural requirements for this ring expansion, we have studied the effect of different bridgehead atoms of the [2.2.1]bicyclic system and the presence of an alkyl substituent at C4. Attempts to perform this ring expansion on a monocyclic analogue have been also explored to evaluate the influence of the bicyclic skeleton on the rearrangement. A detailed mechanistic proposal supported by computational studies is reported.
Pd(II)-Catalyzed Asymmetric Addition of Arylboronic Acids to Aliphatic N-Carbamoyl Hydrazones
(Wiley, 2022) Alberca Manzano, Saúl; Velázquez Muñoz, Marta; Trujillo Sierra, José; Iglesias Sigüenza, Francisco Javier; Fernández Fernández, Rosario Fátima; Lassaletta, José M.; Monge Fernández, David; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía
Catalysts generated by combinations of Pd(TFA)2 and pyridine-hydrazone ligands have been applied to 1,2 addition of arylboronic acids to aliphatic N-carbamoyl (Cbz) hydrazones, affording protected α- aryl monoalkylhydrazines with high enantioselectivities (37-99% ee). Subsequent removal of the benzyloxy carbonyl protecting group provides a direct entry to free monosubstituted hydrazines, key building blocks for the synthesis of appealing 1,2-diaza-heterocycles, aminoacid derived hydrazides and other pharmacophores thereof.
Asymmetric Synthesis of Axially Chiral C N Atropisomers
(Wiley, 2022) Rodríguez Salamanca, Patricia; Fernández Fernández, Rosario Fátima; Hornillos, Valentín; Lassaletta, José M.; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C N atropisom- ers. This review offers an overview of the various method- ologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C N axes. The preparation of different families of C N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.
Aprendizaje basado en problemas para la enseñanza de la química en la universidad
(2019) Maya Díaz, Celia María; Iglesias Sigüenza, Francisco Javier; Universidad de Sevilla. Departamento de Química Inorgánica; Universidad de Sevilla. Departamento de Química orgánica
El objetivo del trabajo es analizar la eficacia de la metodología del aprendizaje basado en problemas (ABP) en una titulación del grupo de las STEM, en concreto en tres asignaturas de 1º, 2º y 3º del Grado en Química de la Universidad de Sevilla. Las clases se convierten para los estudiantes en un lugar de trabajo en grupo en el que deben resolver una serie de cuestiones concatenadas entre sí y que van progresando de menor a mayor complejidad a lo largo de los temas. Para resolver dichas cuestiones deben antes comprender los nuevos conceptos teóricos empleando para ello la bibliografía recomendada por el profesor y las opciones disponibles en internet. Al final de cada tema los alumnos comparan sus resultados con los del profesor y tienen que realizar, de manera individual, una reflexión acerca de sus errores, aciertos, incomprensiones, etc. Los resultados obtenidos al finalizar el curso correspondiente ponen de manifiesto una mejora de los resultados académicos en todas esas asignaturas, una reducción del tiempo de trabajo y un incremento significativo en el grado de satisfacción del alumnado.
Evolution of the catalytic mechanism at the dawn of the Baeyer-Villiger monooxygenases
(Elsevier, 2024-05-28) Yang, Guang; Pećanac, Ognjen; Wijma, Hein J.; Rozeboom, Henriëtte J.; Gonzalo Calvo, Gonzalo de; Fraaije, Marco W.; Mascotti, Maria Laura; Universidad de Sevilla. Departamento de Química orgánica; European Union (UE)
Enzymes are crucial for the emergence and sustenance of life on earth. How they became catalytically active during their evolution is still an open question. Two opposite explanations are plausible: acquiring a mechanism in a series of discrete steps or all at once in a single evolutionary event. Here, we use molecular phylogeny, ancestral sequence reconstruction, and biochemical characterization to follow the evolution of a specialized group of flavoprotein monooxygenases, the bacterial Baeyer-Villiger monooxygenases (BVMOs). These enzymes catalyze an intricate chemical reaction relying on three different elements: a reduced nicotinamide cofactor, dioxygen, and a substrate. Characterization of ancestral BVMOs shows that the catalytic mechanism evolved in a series of steps starting from a FAD-binding protein and further acquiring reactivity and specificity toward each of the elements participating in the reaction. Together, the results of our work portray how an intrinsically complex catalytic mechanism emerged during evolution.
sp2-Iminosugar Azobenzene O-glycosides: Light-sensitive Glycosidase Inhibitors with Unprecedented Tunability and Switching Factors
(Elsevier, 2024) Rivero Barbarroja, Gonzalo; Padilla Pérez, María del Carmen; Maisonneuve, Stéphane; García Moreno, M. Isabel; Tiet, Ben; Vocadlo, David J.; Xie, Juan; García Fernández, José M.; Ortiz Mellet, Carmen; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia, Innovación y Universidades (MICINN). España; European Cooperation in Science and Technology (COST); Natural Sciences and Engineering Research Council of Canada (NSERC); Universidad de Sevilla
The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and β-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human β-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and β-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.
Speeding-up the Determination of Protein-Ligand Affinities by STD NMR: The Reduced Data Set STD NMR Approach (rd-STD NMR)
(American Chemical Society, 2024-01-02) Rocha, Gabriel; Ramírez Cárdenas, Jonathan; Padilla Pérez, María del Carmen; Walpole, Samuel; Nepravishta, Ridvan; García Moreno, M. Isabel; Sánchez Fernández, Elena Matilde; Ortiz Mellet, Carmen; Angulo, Jesús; Muñoz García, Juan Carlos; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla
STD NMR spectroscopy is a powerful ligand-observed NMR tool for screening and characterizing the interactions of small molecules and low molecular weight fragments with a given macromolecule, identifying the main intermolecular contacts in the bound state. It is also a powerful analytical technique for the accurate determination of protein–ligand dissociation constants (KD) of medium-to-weak affinity, of interest in the pharmaceutical industry. However, accurate KD determination and epitope mapping requires a long series of experiments at increasing saturation times to carry out a full analysis using the so-called STD NMR build-up curve approach and apply the “initial slopes approximation”. Here, we have developed a new protocol to bypass this important limitation, which allows us to obtain initial slopes by using just two saturation times and, hence, to very quickly determine precise protein–ligand dissociation constants by STD NMR.
Mechanically Planar-to-Point Chirality Transmission in [2]Rotaxanes
(American Chemical Society, 2024-01-24) Puigcerver, Julio; Marín Luna, Marta; Iglesias Sigüenza, Francisco Javier; Alajarin, Mateo; Martinez-Cuezva, Alberto; Berna, Jose; Universidad de Sevilla. Departamento de Química orgánica; Ministerio de Ciencia e Innovación (MICIN). España; Agencia Estatal de Investigación. España; Fundación Séneca-CARM, Murcia, España.
Herein we describe an effective transmission of chirality, from mechanically planar chirality to point chirality, in hydrogen-bonded [2]rotaxanes. A highly selective mono-N-methylation of one (out of four) amide N atom at the macrocyclic counterpart of starting achiral rotaxanes generates mechanically planar chirality. Followed by chiral resolution, both enantiomers were subjected to a base-promoted intramolecular cyclization, where their interlocked threads were transformed into new lactam moieties. As a matter of fact, the mechanically planar chiral information was effectively transferred to the resulting stereocenters (covalent chirality) of the newly formed heterocycles. Upon removing the entwined macrocycle, the final lactams were obtained with high enantiopurity.

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