De la cicloadición de Huisgen a la química bioortogonal. Un comentario al premio Nobel de Química de 2022 / From the Huisgen cycloaddition to bioorthogonal chemistry. A commentary on the 2022 Nobel Prize in Chemistry

El primer logro de los galardonados con el Premio Nobel de Química de 2022, y en particular de Sharpless, es de tipo conceptual, y consistió en la propuesta del concepto de reacción click dentro de un cuerpo de doctrina general. En una segunda fase, tanto Sharpless como Meldal establecieron la catálisis de la cicloadición 1,3-dipolar de Huisgen por Cu(I), lo que llevó a su reconocimiento de como la primera reacción click y a su empleo generalizado en todos los campos de la química. Estos descubrimientos prepararon el terreno para el descubrimiento por Bertozzi de las reacciones click bioortogonales, aprovechando el incremento de reactividad asociado a la tensión anular de los derivados de ciclooctino. La influencia de estas ideas y descubrimientos ha sido enorme y ha conducido a grandes avances en diversos campos de la Química y la Biología. (AU)

The first achievement of the 2022 Chemistry Nobel Prize awardees, Sharpless in particular, was of a conceptual nature and consisted in the proposal of the click chemistry concept, together with its placement in a broader theoretical frame. In a second phase, both Sharpless and Meldal established the copper(I)-catalyzed conditions that allowed the Huisgen 1,3-dipolar cycloaddition to be recognized as the first click reaction, which was broadly employed in all fields of chemistry. These discoveries laid the ground for the development by Bertozzi of bioorthogonal chemistry on the basis of the increased reactivity associated to ring strain in cyclooctyne derivatives. The influence of these ideas and discoveries has been widespread and has led to innumerable advances in many fields of Chemistry and Biology. (AU)

Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157-Lipoic Acid Hybrids for the Treatment of Alzheimer's Disease.

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman's chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood-brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone-oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.

Aza-CGP37157-lipoic hybrids designed as novel Nrf2-inducers and antioxidants exert neuroprotection against oxidative stress and show neuroinflammation inhibitory properties.

Two multitarget hybrids, derived from an aza-analogue of CGP37157, a mitochondrial Na+ /Ca2+ exchanger antagonist, and lipoic acid were designed in order to combine in a single molecule the antioxidant and Nrf2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The hybrid derivatives showed Nrf2 induction and radical scavenging properties, leading to a good neuroprotective profile against oxidative stress, together with an interesting antineuroinflammatory activity. The results obtained show differences in activity depending on the configuration of the chiral center of LA.

A Sustainable Approach to the Stereoselective Synthesis of Diazaheptacyclic Cage Systems Based on a Multicomponent Strategy in an Ionic Liquid.

The microwave-assisted three-component reactions of 3,5-bis(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones, acenaphthenequinone and cyclic α-amino acids in an ionic liquid, 1-butyl-3-methylimidazolium bromide, occurred through a domino sequence affording structurally intriguing diazaheptacyclic cage-like compounds in excellent yields.

Péptidos, lagartos y diseño de fármacos. Agentes antidiabéticos relacionados con las incretinas / Peptides, lizards and drug design. Incretin-related antidiabetic agents

La diabetes de tipo 2 se ha descrito como una epidemia de ámbito mundial y constituye uno de los mayores desafíos terapéuticos actuales. Las incretinas, en especial GLP-1, son hormonas peptídicas intestinales que estimulan la secreción de insulina y presentan otras acciones beneficiosas, incluyendo una disminución de masa corporal, pero plantean los problemas habituales de los fármacos peptídicos: reducida biodisponibilidad oral y duración de acción muy breve. Se describen en esta revisión los avances recientes en el diseño de antidiabéticos basados en las incretinas, que permiten la superación de dichas limitaciones, así como de inhibidores de su degradación hidrolítica (AU)

Type II diabetes has been described as a world epidemy and constitutes one of the major therapeutic challenges nowadays. Incretins, and GLP-1 in particular, are intestinal peptide hormones that stimulate insulin secretion and show other beneficial actions, including weight loss, but they suffer from the limitations common to most peptide drugs, namely poor oral bioavailability and a very short duration of action. In the present review, we describe recent advances in the design of incretin-based antidiabetic drugs that overcome these limitations, as well as recent work on inhibitors of their hydrolytic degradation (AU)

Nuevos antitumorales de origen marino / New marine antitumour compounds

Aunque los océanos contienen una biodiversidad muy superior a la de la tierra, su explotación desde el punto de vista de la búsqueda de nuevos compuestos químicos apenas se ha iniciado, conociéndose en la actualidad únicamente unos 11.000 productos naturales de origen marino frente a más de 155.000 terrestres. En este discurso se hace una breve revisión general de los principales compuestos antitumorales de origen marino, estudiándose después con mayor detalle los grupos de las piridoacridinas y las triprostatinas. Se hace también una breve revisión de los mecanismos de la acción antitumoral de estos compuestos, entre los que pueden mencionarse los siguientes: inhibición de la angiogénesis, inducción de apoptosis, interrupción del ciclo celular en diversas fases, fragmentación del ADN a través de la generación de especies reactivas de oxígeno, inhibición de enzimas relacionadas con el ADN (topoisomeras, polimerasas, factores de transcripción), interacción con tubulina y microtúbulos y despolarización de la membrana de los lisosomas. Finalmente, se revisan algunas rutas sintéticas hacia dos grupos de productos naturales de origen marino, las piridoacridinas y las triprostatinas

Although oceans cover about 70% of the Earth’s surface and contain most of the biosphere, they are almost unexplored regarding the search for new chemical entities. Thus, only about 11,000 marine natural products are known, in contrast to more than 155,000 terrestrial compounds. In this talk, after a schematic review of the main marine antitumour compounds and their mechanisms of action, the pyridoacridines and tryprostatins are discussed in more detail. The mechanisms of antitumour activity are also briefly reviewed including angiogenesis inhibition, apoptosis induction, interruption of the cell cycle at several stages, DNA fragmentation through the generation of reactive oxygen species, inhibition of DNA-related enzymes (topoisomerases, polymerases, transcription factors), interaction with tubulin and microtubules and lysosome membrane depolarization. Finally, some routes for the synthesis of the pyridoacridines and the tryprostatins are discussed

Synthesis and biological evaluation of new 1,5-diazaanthraquinones with cytotoxic activity.

A series of 1,5-diazaanthraquinone derivatives was synthesized and their in vitro cytotoxic activities were evaluated against several human cancer cell lines. The 1,5-diazaanthraquinone chromophore has been synthesized either on the basis of hetero Diels-Alder reactions involving different quinoline-5,8-diones and alpha,beta-unsaturated aldehyde N,N-dimethylhydrazones or by thermolysis of different arylaminomethylene Meldrum's acid derivatives. Some of these compounds showed cytotoxic activity comparable to that of mitoxantrone against most of the cell lines tested. Compounds 20, 30, 31 and 37 were 4-54 times more potent that mitoxantrone against A549, H116, PSN1 and T98G cancer cell lines but, interestingly, they were 3-16 times less potent against the human breast carcinoma SKBR3. Some structure-activity relationships are described, the most significant one being the increase in cytotoxicity resulting from the introduction of a halogen atom at the C-4 position.

La Química Analítica: aspectos conceptuales y docentes. Evolución, perspectivas actuales y retos de futuro / Concept and scope of Analytical Chemistry. Evolution, trends and futures challenges

Este trabajo reúne una serie de reflexiones en el campo de la Química Analítica actual, tanto en España como en el resto mundo. Se comentan algunos de los aspectos relativos a la inquietud actual por definir el campo de actuación de la Química Analítica. Se analizan las maneras en las que la Química Analítica debe responder a los problemas diarios en la sociedad actual. Desde esta perspectiva, se analiza su evolución y las tendencias actuales, para lo cual se toma como referencia la gran inversión realizada en instrumentación analítica, tanto por los laboratorios privados como por los públicos. Se pone especial énfasis en el incremento en el número de publicaciones de contenido analítico en revistas de reconocido prestigio internacional, gracias al trabajo de los profesores e investigadores en universidades y centros de investigación. Estos aspectos han favorecido la transmisión de conocimientos en las universidades españolas, potenciando la formación de los futuros profesionales farmacéuticos en este campo (AU)