“On water” reactivity between carbohydrate-derived nitroalkenes and furans

Las reacciones ecológicas "sobre el agua" de derivados de carbohidratos con nitroalkenes furano, 2-methylfuran y furfural N,N-dimethylhydrazone han sido investigados bajo diferentes métodos de mezcla, como un agitador magnético y un agitador de acción con la muñeca. Los furyl derivados cíclicos y acíclicos de los carbohidratos fueron obtenidos con elevada diastereo-selectividad.Eco-friendly “on water” reactions of carbohydrate-derived nitroalkenes with furan, 2-methylfuran and furfural N,N-dimethylhydrazone have been investigated under different mixing methods, such as a magnetic stirrer and a wrist-action shaker. Cyclic and acyclic furyl derivatives from carbohydrates were obtained with high diastereoselectivity.• Gobierno de Extremadura y Fondos FEDER. Ayuda a Grupos de Investigación GR15022 • Universidad de Extremadura. Plan de Iniciación a la Investigación, Desarrollo Tecnológico e Innovación 2015, para Verónica Luque AgudopeerReviewe

Síntesis ecosostenible de heterociclos con potencial actividad biológica

En la presente Tesis Doctoral se explora el uso de metodologías ecosostenibles para la síntesis de heterociclos derivados de carbohidratos, a los que posteriormente se les ha evaluado su potencial actividad biológica. Por un lado, se han empleado las condiciones “on water” tanto para llevar a cabo las cicloadiciones Diels-Alder entre diversas maleimidas y furanos como para estudiar la reactividad de dos 2-nitro-D-glicales. Los productos de reacción obtenidos en el primer caso son 5,6-deshidronorcantarimidas, compuestos con potenciales propiedades de interés biológico, tales como actividad insecticida o poder reductor. Si bien parte de los productos de la serie son ya conocidos, la nueva ruta sintética aquí planteada presenta varias ventajas, como son unas condiciones de reacción más suaves, menores tiempos de reacción, altos rendimientos y, en algunos casos, una mayor estereoespecificidad de los procesos. Sin embargo, experimentalmente, los productos obtenidos no mostraron actividad insecticida frente a la larva de polilla Helicoverpa armigera. Resulta interesante estudiar cómo afectan las condiciones “on water” a la reactividad de 2-nitro-D-glicales, ya que estas sustancias no presentan la reactividad típica de las nitroolefinas deficientes de electrones. Del mismo modo, se ha llevado a cabo también un estudio sobre la influencia del método de agitación sobre la propia reactividad “on water”. En el caso concreto de las reacciones entre furanos y estos 2-nitro-D-glicales, se ha determinado que la agitación permite “dirigir” la transformación hacia la formación de unos productos u otros (aductos de Michael acíclicos/derivados de sustitución en C3). Finalmente, se ha propuesto un mecanismo de reacción apoyado en los hechos experimentales para explicar estos resultados. Por otro lado, se han sintetizado 3-nitro y 3-formil-1,2-dihidroquinolinas y 3-nitro y 3-formilquinolinas con un fragmento de carbohidrato unido a C2 mediante reacciones llevadas a cabo en ausencia de disolvente y con alúmina neutra como catalizador. Estos procesos no son sólo de interés por la asimetría que induce la propia cadena, sino porque este tipo de compuestos presentan actividad antiproliferativa. Así, se ha evaluado ésta frente a un panel de seis líneas celulares tumorales, encontrándose valores de GI50 moderados y, en algunos casos concretos, mejores que los de los patrones farmacológicos utilizados como referencia. También se han llevado a cabo adiciones de Michael entre indol y pirrol y las 1-formil-3-nitro-1,2-dihidroquinolinas sintetizadas, en ausencia de disolvente y con catálisis de alúmina básica, aislándose los dos rotámeros del mismo diastereoisómero de adición, de manera que ésta es estereoespecífica.This Work explores the use of eco-friendly methodologies for the synthesis of heterocycles derived from carbohydrates, which have subsequently been evaluated for their potential biological activity. On the one hand, "on water" conditions have been used both to carry out the Diels-Alder cycloaddition between various maleimides and furans and to study the reactivity of two 2-nitro-D-glycals. Products obtained in the first case are 5,6-dehydronorcantarimides, compounds with potential properties of biological interest, such as insecticidal activity or reducing power. Although some of the products in the series are already known, the novel synthetic route presented has several advantages, such as softer reaction conditions, shorter reaction times, higher yields and, in some cases, greater stereospecificity of processes. However, experimentally, products showed no insecticidal activity against Helicoverpa armigera moth larva. It is interesting to study how the “on water” conditions affect the reactivity of 2-nitro-D-glycals, since these substances do not exhibit the typical reactivity of electron-deficient nitroolefins. In the same way, a study about the influence of the stirring method on the own “on water” reactivity has also been carried out. In the specific case of the reactions between furans and these 2-nitro-D-glycals, it has been determined that the stirring allows to "direct" the transformation towards the formation of some products or another (Michael acyclic adducts / C3 substituted derivatives). Finally, a reaction mechanism based on experimental facts has been proposed to explain these results. On the other hand, 3-nitro and 3-formyl-1,2-dihydroquinolines and 3-nitro and 3-formylquinolines have been synthesized with a carbohydrate fragment bound to C2 by reactions carried out in the absence of solvent and with neutral alumina as catalyst. These processes are not only of interest because of the asymmetry induced by the chain itself, but because these types of compounds have antiproliferative activity. Thus, it has been evaluated against a panel of six tumor cell lines, with GI50 values being moderate and, in some specific cases, better than those of the pharmacological standards used as reference. Michael additions have also been made between indole and pyrrole and the synthesized 1-formyl-3-nitro-1,2-dihydroquinolines, in the absence of solvent and with basic alumina catalysis, the two rotamers of the same diastereosomer were isolated, so reaction is stereospecific.Plan de iniciación a la Investigación, Desarrollo Tecnológico e Innovación 2013. Acción II (Becas de Investigación, Desarrollo Tecnológico e Innovación para no Doctores de un año de duración). Universidad de Extremadura. - Plan de iniciación a la Investigación, Desarrollo Tecnológico e Innovación 2014. Acción II (Becas de Investigación, Desarrollo Tecnológico e Innovación para no Doctores de un año de duración). Universidad de Extremadura. - Plan de iniciación a la Investigación, Desarrollo Tecnológico e Innovación 2015. Acción II (Becas de Investigación, Desarrollo Tecnológico e Innovación para no Doctores de un año de duración). Universidad de Extremadura y Grupo Banco Santander. - Plan de iniciación a la Investigación, Desarrollo Tecnológico e Innovación 2016. Acción II (Becas de Investigación, Desarrollo Tecnológico e Innovación para no Doctores de un año de duración). Universidad de Extremadura y Grupo Banco Santander. - Gobierno de Extremadura-Ayuda a Grupos de Investigación Catalogados y FEDER (GR15022)

Influence of Solvent and Substrate on Hydrophobicity of PLA Films

The study of the surface properties of materials is key in determining whether the material will be suitable for medical purposes. One of these properties is hydrophobicity, which is important when assessing its behavior against bacterial adhesion. In this work, we have studied the influence of the solvent (chloroform, acetone, and tetrahydrofuran) and the substrate (glass, PTFE, silicone, and Ti6Al4V) on which polylactic acid is deposited in solution to manufacture films by solvent-casting. Thus, it has been found that there are no significant differences in hydrophobicity and surface tension among the solvents evaluated, but there are significant differences with respect to the substrates: PLA films casted on silicone are hydrophobic, while those casted on the rest of the substrates are hydrophilic. This is related to the fact that the silicone interacts with the polymer modifying its spatial arrangement, exposing its methyl groups towards the interface with the air. In this way, it has been shown that, when manufacturing PLA films, it is important to choose the right surface on which to deposit them, depending on their desired function

Aging of Solvent-Casting PLA-Mg Hydrophobic Films: Impact on Bacterial Adhesion and Viability

Biomaterials used for the manufacture of biomedical devices must have suitable surface properties avoiding bacterial colonization and/or proliferation. Most biomaterial-related infections start during the surgery. Bacteria can begin colonization of the surface of a device right after implantation or in the next few hours. This time may also be sufficient to begin the deterioration of a biodegradable implant. This work explores the surface changes that hydrophobic films of poly(lactic) acid reinforced with Mg particles, prepared by solving-casting, undergone after in vitro degradation at different times. Hydrophobicity, surface tension, zeta potential, topography, and elemental composition were obtained from new and aged films. The initial degradation for 4 h was combined with unspecific bacterial adhesion and viability tests to check if degraded films are more or less susceptible to be contaminated. The degradation of the films decreases their hydrophobicity and causes the appearance of a biocompatible layer, composed mainly of magnesium phosphate. The release of Mg2+ is very acute at the beginning of the degradation process, and such positive charges may favor the electrostatic approach and attachment of Staphylococci. However, all bacteria attached on the films containing Mg particles appeared damaged, ensuring the bacteriostatic effect of these films, even after the first hours of their degradation

Bacterial Response to the Surface Aging of PLA Matrices Loaded with Active Compounds

The use of active components in biomaterials improves the properties of existing ones and makes it possible to obtain new devices with antibacterial properties that prevent infections after implantation, thus guaranteeing the success of the implant. In this work, cetyltrimethylammonium bromide (CTAB) and magnesium particles were incorporated into polylactic acid (PLA) films to assess the extent to which progressive aging of the new surfaces resists bacterial colonization processes. For this purpose, the films’ surface was characterized by contact angle measurements, ToF-SIMS and AFM, and adhesion, viability and biofilm growth of Staphylococcus epidermidis bacteria on these films were also evaluated. The results show that the inclusion of Mg and CTAB in PLA films changes their surface properties both before and after aging and also modifies bacterial adhesion on the polymer. Complete bactericidal activity is exhibited on non-degraded films and films with CTAB. This antibacterial behavior is maintained after degradation for three months in the case of films containing a higher amount of CTAB

PLA-Mg film degradation under in vitro environments supplemented with glucose and/or ketone bodies

Materials used for the manufacture of implants may suffer alterations in their surface properties as a result of continuous contact with physiological fluids. Moreover, in biodegradable and bioabsorbable materials, such as polylactic acid (PLA), these changes may be more accentuated, and their biological response may be affected by the presence of proteins, enzymes or other compounds of an oxidizing character. This research proposes to study the degradation of PLA in a close-to-reality environment by supplementing the physiological buffer m-SBF with concentrations of glucose and ketone bodies of healthy individuals. To this end, parameters such as hydrophobicity, surface tension, topography and surface chemical composition of PLA films and PLA films doped with magnesium particles after degradation were evaluated to determine how these components influence these properties compared to degradation in standard buffer. The presence of glucose and/or ketone bodies in the degradation medium of PLA doped with magnesium particles altered the composition of the salt layers absorbed on the surface of the material due to the action of gluconate and/or hydroxybutyrate anions, which were able to coordinate with ions from the solution as well as Mg2+ cations from polymer degradation. The salt accumulation on polymeric films changes the surface mechanical response increasing the Young's modulus after degradation

Synthesis and antiproliferative activity of new 2-glyco-3-nitro-2<i>H</i>-chromenes

3-nitro-2H-chromenes and derivatives are compounds with diverse biological activity, among them, new 2-glyco-3-nitro-2H-chromenes have been prepared by one-pot oxa-Michael-Henry-dehydration reactions between carbohydrate-derived nitroalkenes and several salicylaldehydes, using a minimal amount of solvent and DBU as catalyst. The antiproliferative activity of these new compounds has been evaluated against a panel of six human solid tumor cell lines, and compared to pharmacological reference compounds, finding that their activities are in the low micromolar range and that some of them are more effective than the standards.</p