RESUMEN

Large bone defects are a significant health problem today with various origins, including extensive trauma, tumours, or congenital musculoskeletal disorders. Tissue engineering, and in particular bone tissue engineering, aims to respond to this demand. As such, we propose a specific model based on Elastin-Like Recombinamers-based click-chemistry hydrogels given their high biocompatibility and their potent on bone regeneration effect conferred by different bioactive sequences. In this work we demonstrate, using biochemistry, histology, histomorphometry and imaging techniques, the biocompatibility of our matrix and its potent effect on bone regeneration in a model of bone parietal lesion in female New Zealand rabbits.

Asunto(s)

Materiales Biocompatibles , Regeneración Ósea , Elastina , Hidrogeles , Ingeniería de Tejidos , Animales , Femenino , Conejos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Regeneración Ósea/efectos de los fármacos , Química Clic/métodos , Elastina/química , Hidrogeles/química , Hidrogeles/farmacología , Ingeniería de Tejidos/métodos , Andamios del Tejido/química

RESUMEN

This study focused on synthesizing and characterizing PEGylated amphiphilic block copolymers with pendant linoleic acid (Lin) moieties as an alternative to enhance their potential in drug delivery applications. The synthesis involved a two-step process, starting with ring-opening polymerization of ε-caprolactone (CL) and propargylated cyclic carbonate (MCP) to obtain PEG-b-P(CL-co-MCP) copolymers, which were subsequently modified via click chemistry. Various reaction conditions were explored to improve the yield and efficiency of the click chemistry step. The use of anisole as a solvent, N-(3-azidopropyl)linoleamide as a substrate, and a reaction temperature of 60°C proved to be highly efficient, achieving nearly 100% conversion at a low catalyst concentration. The resulting copolymers exhibited controlled molecular weights and low polydispersity, confirming the successful synthesis. Furthermore, click chemistry allows for the attachment of Lin moieties to the copolymer, enhancing its hydrophobic character, as deduced from their significantly lower critical micelle concentration than that of traditional PEG-b-PCL systems, which is indicative of enhanced stability against dilution. The modified copolymers exhibited improved thermal stability, making them suitable for applications that require high processing temperatures. Dynamic light scattering and transmission electron microscopy confirmed the formation of micellar structures with sizes below 100 nm and minimal aggregate formation. Additionally, 1H NMR spectroscopy in deuterated water revealed the presence of core-shell micelles, which provided higher kinetic stability against dilution.

Asunto(s)

Química Clic , Polietilenglicoles , Polimerizacion , Química Clic/métodos , Polietilenglicoles/química , Ácido Linoleico/química , Micelas , Interacciones Hidrofóbicas e Hidrofílicas , Tensoactivos/química , Tensoactivos/síntesis química , Peso Molecular

RESUMEN

OBJECTIVE: To develop N-(levodopa) chitosan derivatives through click chemistry to study their effect in brain cells.Significance: This study presents a proof-of-concept that macromolecules such as N-(Levodopa) chitosan derivatives traverse brain cell membranes and induce biomedical functionalities. METHODS: Through click chemistry, we developed N-(levodopa) chitosan derivatives. They were physically and chemically characterized by FT-IR, 1H-NMR, TGA and Dynamic Light Scattering analyses. Solution and nanoparticles of N-(levodopa) chitosan derivatives were tested in primary cell cultures from the postnatal rat olfactory bulb, substantia nigra and corpus callosum. Ca2+ imaging and UPLC experiments were used to investigate if the biomaterial modulated the brain cell physiology. RESULTS: N-(levodopa) chitosan derivatives induced intracellular Ca2+ responses in primary cell cultures of the rat brain. UPLC experiments indicated that levodopa attached to chitosan was converted into dopamine by brain cells. CONCLUSION: The present study shows that N-(levodopa) chitosan may be useful to develop new treatment strategies, which could serve as molecular reservoirs of biomedical drugs to treat degenerative disorders of the nervous system.

Asunto(s)

Quitosano , Levodopa , Ratas , Animales , Levodopa/farmacología , Quitosano/química , Química Clic/métodos , Espectroscopía Infrarroja por Transformada de Fourier , Encéfalo

RESUMEN

The derivatization of chitosan (CS) is widely exploited to endow this polysaccharide with enhanced physicochemical and biological properties. Beyond the synthetic route, the nature of the compounds used to functionalize the CS-derivatives exerts a pivotal role in their final properties. Making use of a simple "click" reaction, we synthesized for the first time an organoselenium-CS derivative through a 1,2,3-triazole formation. The product (CS-TSe) was characterized in detail by FTIR, NMR (1H, 13C, and 77Se) and UV-Vis techniques, and SEM microscopy. The antioxidant activity of CS-TSe was examined by ABTS+ and DPPH (free radical-scavenging) assays. Experimentally, it was demonstrated that CS-TSe has superior antioxidant activity compared with raw CS and "free" organoselenium compound, suggesting a benign and synergistic effect due to the derivatization. In short, the antioxidant property of CS-TSe combined with the other attractive properties of CS and selenium could be useful in the formulation of advanced materials for biomedical and packaging applications.

Asunto(s)

Antioxidantes/síntesis química , Quitosano/análogos & derivados , Química Clic/métodos , Compuestos de Organoselenio/química , Triazoles/química

RESUMEN

Many species of aquatic worms, including members of the phyla Nemertea, Annelida, Platyhelminthes, and Xenacoelomorpha, can regenerate large parts of their body after amputation. In most species, cell proliferation plays key roles in the reconstruction of lost tissues. For example, in annelids and flatworms, inhibition of cell proliferation by irradiation or chemicals prevents regeneration. Cell proliferation also plays crucial roles in growth, body patterning (e.g., segmentation) and asexual reproduction in many groups of aquatic worms. Cell proliferation dynamics in these organisms can be studied using immunohistochemical detection of proteins expressed during proliferation-associated processes or by incorporation and labeling of thymidine analogues during DNA replication. In this chapter, we present protocols for labeling and quantifying cell proliferation by (a) antibody-based detection of either phosphorylated histone H3 during mitosis or proliferating cell nuclear antigen (PCNA) during S-phase, and (b) incorporation of two thymidine analogues, 5'-bromo-2'-deoxyuridine (BrdU) and 5'-ethynyl-2'-deoxyuridine (EdU), detected by immunohistochemistry or inorganic "click" chemistry, respectively. Although these protocols have been developed for whole mounts of small (<2 cm) marine and freshwater worms, they can also be adapted for use in larger specimens or tissue sections.

Asunto(s)

Anélidos/fisiología , Platelmintos/fisiología , Animales , Anélidos/citología , Ciclo Celular , Proliferación Celular , Química Clic/métodos , Inmunohistoquímica/métodos , Platelmintos/citología , Regeneración , Fijación del Tejido/métodos

RESUMEN

A novel strategy via the triple process (multicomponent reactions (MCR)-domino)/tandem was developed for the synthesis of restricted and constrained bis-1,2,3-triazole-linked pyrrolo[3,4-b]pyridine peptidomimetics dimers in overall yields of 20-55%. This strategy allows the construction of six heterocycles in two stages of the reaction.

Asunto(s)

Química Clic/métodos , Reacción de Cicloadición/métodos , Dimerización , Peptidomiméticos/síntesis química , Cromatografía en Capa Delgada , Cianuros/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Piridinas , Espectrometría de Masa por Ionización de Electrospray , Especificidad por Sustrato , Triazoles

RESUMEN

From a materials science perspective, herein we present the design and synthesis of six macromolecular carbohydrate derivatives, obtained by combining the native cyclic oligosaccharide ßCD and dendritic poly(ester) moieties, coupled by CuAAc click reactions, in a convergent fashion. We envisioned two structural variables to promote the formation of inclusion complexes (ICs) with the anti-parasitic drug Albendazole, the degree of substitution on the ßCD (mono or hepta-substitution) and the dendritic generation (from first to third). In terms of synthetic effort and cost, the mono-substituted ßCD derivatives were obtained in more approachable experimental conditions in comparison to the ßCD dendrimers (hepta-substituted macrocycle). The six dendritic derivatives were more soluble in water and showed better complexation capacity than native ßCD. For both, mono and hepta-substituted ßCD, we observed that the amount of encapsulated ABZ increases when the dendron generation increases. Interestingly, different degrees of substitution (mono and hepta) lead comparable results of ABZ complexation. In conclusion, the encapsulation performance and the consequent solubility enhancement, make these molecular containers excellent materials to positively impact the therapeutic desirability of ABZ.

Asunto(s)

2-Hidroxipropil-beta-Ciclodextrina/química , Albendazol/química , Química Clic/métodos , Portadores de Fármacos , Sustancias Macromoleculares , Solubilidad , Agua/química , beta-Ciclodextrinas

RESUMEN

Protecting group-free synthesis of 1,2:5,6-di-anhydro-D-mannitol, followed by ring opening with propargylamine and subsequent ring closure produced a separable mix of piperidine N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and azepane N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol. In O-acetylated form, these two building blocks were subjected to CuAAC click chemistry with a panel of three differently azide-substituted glucose building blocks, producing iminosugar pseudo-disaccharides in good yield. The overall panel of eight compounds, plus 1-deoxynojirimycin (DNJ) as a benchmark, was evaluated as prospective inhibitors of almond ß-glucosidase, yeast α-glucosidase and barley ß-amylase. The iminosugar pseudo-disaccharides showed no inhibitory activity against almond ß-glucosidase, while the parent N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol likewise proved to be inactive against yeast α-glucosidase. Inhibitory activity could be reinstated in the former series by appropriate substitution on nitrogen. The greater activity of the piperidine could be rationalized based on docking studies. Further, potent inhibition of ß-amylase was observed with compounds from both the piperidine and azepane series.

Asunto(s)

Inhibidores Enzimáticos/síntesis química , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Iminoazúcares/síntesis química , Piperidinas/síntesis química , Triazoles/síntesis química , alfa-Glucosidasas/química , beta-Amilasa/química , beta-Glucosidasa/química , 1-Desoxinojirimicina/química , Azidas/química , Química Clic/métodos , Disacáridos/química , Inhibidores Enzimáticos/química , Glucosa/química , Compuestos Heterocíclicos con 1 Anillo/química , Hordeum/química , Hordeum/enzimología , Iminoazúcares/química , Manitol/química , Pargilina/análogos & derivados , Pargilina/química , Piperidinas/química , Propilaminas/química , Prunus dulcis/química , Prunus dulcis/enzimología , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimología , Triazoles/química , beta-Amilasa/antagonistas & inhibidores , beta-Glucosidasa/antagonistas & inhibidores

RESUMEN

A series of 1,2,3-triazolylsterols was prepared from pregnenolone through reductive amination and copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry). The newly generated stereocenter of the key propargylamino intermediate provided a mixture of diastereomers which were separated chromatographically, and the configuration of the R isomer was determined by X-ray crystallography. Ten triazolyl sterols were prepared, and the products and intermediates were screened in vitro against different parasites, with some compounds presenting IC50 values in the low micromolar range against Leishmania donovani.

Asunto(s)

Antiprotozoarios/farmacología , Química Clic/métodos , Leishmania donovani/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Esteroles/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Química Farmacéutica/métodos , Cristalografía por Rayos X , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estructura Molecular , Esteroles/síntesis química , Esteroles/química

RESUMEN

The palladium catalyzed cross-coupling reaction of phenyltrifluoroborate with a chemoenzymatically derived bromoazidoconduritol, combined with 1,3-dipolar cycloaddition, with a variety of alkynes is described. Fourteen new compounds were synthesized in moderate to good yields. The click chemistry reaction can be effected by using sodium ascorbate and CuSO(4) · 5H(2)O as catalyst in toluene-H(2)O at room temperature.

Asunto(s)

Biocatálisis , Química Clic/métodos , Ciclitoles/química , Paladio/química , Ciclitoles/síntesis química , Dioxigenasas/metabolismo , Pseudomonas putida/enzimología