RESUMEN
Meiotic recombination between homologous chromosomes initiates via programmed DNA double-strand breaks (DSBs), generated by complexes comprising Spo11 transesterase plus accessory proteins. DSBs arise concomitantly with the development of axial chromosome structures, where the coalescence of axis sites produces linear arrays of chromatin loops. Recombining DNA sequences map to loops, but are ultimately tethered to the underlying axis. How and when such tethering occurs is currently unclear. Using ChIPchip in yeast, we show that Spo11-accessory proteins Rec114, Mer2, and Mei4 stably interact with chromosome axis sequences, upon phosphorylation of Mer2 by S phase Cdk. This axis tethering requires meiotic axis components (Red1/Hop1) and is modulated in a domain-specific fashion by cohesin. Loss of Rec114, Mer2, and Mei4 binding correlates with loss of DSBs. Our results strongly suggest that hotspot sequences become tethered to axis sites by the DSB machinery prior to DSB formation.
Asunto(s)
Endodesoxirribonucleasas/metabolismo , Meiosis , Recombinación Genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/genética , Cromosomas Fúngicos/metabolismo , Roturas del ADN de Doble Cadena , Unión Proteica , Saccharomyces cerevisiae/metabolismoRESUMEN
Breast cancer is one of the leading causes of death in the female population because of the resistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubility and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxycurcumin magnesium complex (DiMeOC-Mg, (4)) with beta-cyclodextrin (DiMeOC-Mg-BCD, (5)) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media phosphate buffer saline (PBS) was improved by a factor of 6x over the free metal complex (4). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and signal transducer and activator of transcription-3 (STAT3) expression levels on MD Anderson metastasis breast-231 cancer (MDA-MB-231) cell lines. Results of an antitumor assay in an in ovo model showed up to 30% inhibition of tumor growth for breast cancer (MDA-MB-231) when using (5) (0.650 mg/kg dose) and 17.29% inhibition with the free homoleptic metal complex (1.5 mg/kg dose, (4)). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new compound (5) exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.
Asunto(s)
Antineoplásicos , Curcumina , Curcumina/análogos & derivados , Magnesio , beta-Ciclodextrinas , beta-Ciclodextrinas/química , Curcumina/farmacología , Curcumina/química , Curcumina/farmacocinética , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Magnesio/química , Apoptosis/efectos de los fármacos , Femenino , Línea Celular Tumoral , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Movimiento Celular/efectos de los fármacos , Solubilidad , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Embrión de Pollo , Metaloproteinasa 9 de la Matriz/metabolismoRESUMEN
The crystal structure determination of metal complexes of curcuminoids is a relevant topic to assess their unequivocal molecular structure. We report herein the first two X-ray crystal structures of homoleptic metal complexes of a curcuminoid, namely Dimethoxycurcumin (DiMeOC), with gallium and indium. Such successful achievement can be attributed to the suppression of interactions from the phenolic groups, which favor an appropriate molecular setup, rendering Dimethoxycurcumin gallium ((DiMeOC)2-Ga) and Dimethoxycurcumin indium ((DiMeOC)3-In) crystals. Surprisingly, the conformation of ligands in the crystal structures shows differences in each metal complex. Thus, the ligands in the (DiMeOC)2-Ga complex show two different conformers in the two molecules of the asymmetric unit. However, the ligands in the (DiMeOC)3-In complex exhibit three different conformations within the same molecule of the asymmetric unit, constituting the first such case described for an ML3 complex. The cytotoxic activity of the (DiMeOC)2-Ga complex is 4-fold higher than cisplatin against the K562 cell line and has comparable activity towards U251 and PC-3 cell lines. Interestingly, this complex exhibit three times lesser toxicity than cisplatin and even slightly lesser cytotoxicity than curcumin itself.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Galio , Galio/farmacología , Galio/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Cisplatino , Indio/química , Diarilheptanoides , Línea Celular Tumoral , Ligandos , Antineoplásicos/farmacologíaRESUMEN
We report herein the synthesis and characterization of three heterocyclic curcuminoid ligands and their homoleptic metal complexes with magnesium and copper. Thus, N-methyl-2-pyrrolecarboxaldehyde, Furan-2-carboxaldehyde, and 2-Thiophenecarboxaldehyde were condensed with 2,4-pentanedione-boron trioxide complex. The first N-methyl-2-pyrrole curcuminoid and its Mg(II) complex are reported. All curcuminoid ligands and their corresponding metal complexes were characterized by infrared spectroscopy (IR), liquid state nuclear magnetic resonance (LSNMR), electron paramagnetic resonance (EPR), mass spectrometry (MS) and single crystal X-ray diffraction (SCXRD). The ThiopheneCurc-Cu (9) constitutes the first case of a "conformationally-heteroleptic" complex. The unique six-peaks star arrangement for the ThiopheneCurc ligand derived from the supramolecular description is reported. The metal complexes of FuranCurc-Mg (5) and ThiopheneCurc-Cu (9) have a good antioxidant effect (IC50 = 11.26 ± 1.73 and 10.30 ± 0.59 µM), three and two times higher than their free ligands respectively. Additionally, (5) shows remarkable cytotoxicity against colon cancer adenocarcinoma cell line HCT-15, comparable to that of cisplatin, with a negligible toxic effect in vitro towards a healthy monkey kidney cell line (COS-7).
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Diarilheptanoides , Complejos de Coordinación/química , Cisplatino , Antioxidantes/farmacología , Espectroscopía de Resonancia por Spin del Electrón , Cobre/química , Cristalografía por Rayos X , Ligandos , Antineoplásicos/químicaRESUMEN
The first single crystal structure of the homoleptic copper (II) ML2 complex (M=Cu (II), L = curcumin) was obtained and its structure was elucidated by X-ray diffraction showing a square planar geometry, also confirmed by EPR. The supramolecular arrangement is supported by C-H···O interactions and the solvent (MeOH) plays an important role in stabilizing the crystal packing Crystallinity was additionally assessed by XRD patterns. The log P value of the complex (2.3 ± 0.15) was determined showing the improvement in water solubility. The cytotoxic activity of the complex against six cancer cell lines substantially surpasses that of curcumin itself, and it is particularly selective against leukemia (K562) and human glioblastoma (U251) cell lines, with similar antioxidant activity to BHT. This constitutes the first crystal structure of pristine curcumin complexed with a metal ion.
RESUMEN
The worldwide known and employed spice of Asian origin, turmeric, receives significant attention due to its numerous purported medicinal properties. Herein, we report an optimized synthesis of curcumin and symmetric curcuminoids of aromatic (bisdemethoxycurcumin) and heterocyclic type, with yields going from good to excellent using the cyclic difluoro-boronate derivative of acetylacetone prepared by reaction of 2,4-pentanedione with boron trifluoride in THF (ca. 95%). The subsequent cleavage of the BF2 group is of significant importance for achieving a high overall yield in this two-step procedure. Such cleavage occurs by treatment with hydrated alumina (Al2O3) or silica (SiO2) oxides, thus allowing the target heptanoids obtained in high yields as an amorphous powder to be filtered off directly from the reaction media. Furthermore, crystallization instead of chromatographic procedures provides a straightforward purification step. The ease and efficiency with which the present methodology can be applied to synthesizing the title compounds earns the terms "click" and "unclick" applied to describe particularly straightforward, efficient reactions. Furthermore, the methodology offers a simple, versatile, fast, and economical synthetic alternative for the obtention of curcumin (85% yield), bis-demethoxycurcumin (78% yield), and the symmetrical heterocyclic curcuminoids (80-92% yield), in pure form and excellent yields.
Asunto(s)
Curcumina , Curcumina/química , Diarilheptanoides , Dióxido de Silicio , Curcuma/química , Extractos Vegetales/químicaRESUMEN
We report a practical two-step approach involving a Ugi 4-CR/ azide-alkyne cycloaddition for the synthesis of biaryl-containing cyclophanes. The series represents an extension of our previously reported macrocycles as an effort to enhance the anti-proliferative activity of this scaffold. In this variant, we incorporate a biphenyl moiety in the framework, thus enhancing the macrocycle size, lipophilicity, and structural diversity. Macrocycles were tested against different cell lines, being more cytotoxic against prostate (PC-3 and DU-145) and breast (MCF-7) tumor cells. Gratifyingly, the most active compound showed a significative enhancement of PC-3 growth inhibition with respect to our previous series, reaffirming the potential anti-proliferative activity of this kind of cyclophanes.
Asunto(s)
Antineoplásicos/síntesis química , Éteres Cíclicos/síntesis química , Piperidinas/síntesis química , Triazoles/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reacción de Cicloadición , Ensayos de Selección de Medicamentos Antitumorales , Éteres Cíclicos/farmacología , Humanos , Piperidinas/farmacología , Relación Estructura-ActividadRESUMEN
Curcumin, the most important secondary metabolite isolated from Curcuma longa, is known for its numerous purported therapeutic properties and as a natural dye. Herein, based on curcumin's intrinsic fluorescence, a search for improved curcumin-based fluorophores was conducted. Within the set of semi-synthetic curcumin derivatives i.e. mono (1), di (2), tri (3), tetra (4) benzylated and dibenzyl-fluoroborate (5), the fluorescence properties of 2 and 5 in solution outstood with a two-fold quantum yield compared to curcumin. Furthermore, all benzylated derivatives showed a favorable minimal cytotoxic activity upon screening at 25 µM against human cancer and non-tumoral COS-7 cell lines, with a reduction of its cytotoxic effect related to the degree of substitution. Fluorophores 2 and 5 are versatile bioimaging tools, as revealed by Confocal Fluorescence Microscopy (CFM), and showed permeation of living cell membranes of astrocytes and astrocytomas. When 2 is excited with a 405- (blue) or 543-nm (green) laser, it is possible to exclusively and intensively visualize the nucleus. However, the fluorescence emission fades as the laser wavelength moves towards the red region. In comparison, 5 allows selective visualization of cytoplasm when a 560-nm laser is used, showing emission in the NIR region, while it is possible to exclusively observe the nucleus at the blue region with a 405-nm laser.
Asunto(s)
Núcleo Celular , Citoplasma , Diarilheptanoides/química , Diarilheptanoides/farmacología , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Imagen Molecular , Núcleo Celular/metabolismo , Curcumina/química , Curcumina/farmacología , Citoplasma/metabolismo , Modelos Moleculares , Conformación Molecular , Imagen Molecular/métodos , Estructura MolecularRESUMEN
We report herein the synthesis and crystal structures of five new homoleptic copper complexes of curcuminoids. The scarcity of reports of homoleptic complex structures of curcuminoids is attributed to the lack of crystallinity of such derivatives, and therefore, their characterization by single crystal X-ray diffraction is rare. The ligand design suppressing the phenolic interaction by esterification or etherification has afforded a significant increase in the number of known crystal structures of homoleptic metal complexes of curcuminoids revealing more favorable crystallinity. The crystal structures of the present new copper complexes show four-fold coordination with a square planar geometry. Two polymorphs were found for DiBncOC-Cu when crystallized from DMF. The characterization of these new complexes was carried out using infrared radiation (IR), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and single crystal X-ray diffraction (SCXRD) and the antioxidant and cytotoxic activity of the obtained complexes was evaluated.
Asunto(s)
Complejos de Coordinación/química , Cobre/química , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Relación Dosis-Respuesta a Droga , Ligandos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Ratas , Análisis EspectralRESUMEN
At the present time, scientists place a great deal of effort worldwide trying to improve the therapeutic potential of metal complexes of curcumin and curcuminoids. Herein, the synthesis of four homoleptic metal complexes with diacetylcurcumin (DAC), using a ligand designed to prevent the interaction of phenolic groups, rendering metal complexes through the ß-diketone functionality, is reported. Due to their physiological relevance, we used bivalent magnesium, zinc, copper, and manganese for complexation with DAC. The resulting products were characterized by ultraviolet-visible (UV-Vis), fluorescence spectroscopy, infrared spectroscopy (IR), liquid and solid-state nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), magnetic moment, mass spectrometry (MS), single crystal, and powder X-ray diffraction (SCXRD and PXRD). Crystallization was achieved in dimethylsulfoxide (DMSO) or N,N-dimethylformamide (DMF) as triclinic systems with space group P-1, showing the metal bound to the ß-diketone function, while the 1H-NMR confirmed the preference of the enolic form of the ligand. Single crystal data demonstrated a 1:2 metal:ligand ratio. The inhibition of lipid peroxidation was evaluated using the thiobarbituric acid reactive substance assay (TBARS). All four metal complexes (Mg, Zn, Cu, and Mn) exhibited good antioxidant effect (IC50 = 2.03 ± 0.27, 1.58 ± 0.07, 1.58 ± 0.15 and 1.24 ± 0.10 µM respectively) compared with butylated hydroxytoluene (BHT) and α-tocopherol. The cytotoxic activity in human cancer cell lines against colon adenocarcinoma (HCT-15), mammary adenocarcinoma (MCF-7), and lung adenocarcinoma (SKLU-1) was found comparable ((DAC)2Mg), or ca. 2-fold higher ((DAC)2Zn) than cisplatin. The acute toxicity assays indicate class 5 toxicity, according to the Organization for Economic Co-operation and Development (OECD) guidelines at doses of 3 g/kg for all complexes. No mortality or changes in the behavior of animals in any of the treated groups was observed. A therapeutic potential can be envisaged from the relevant cytotoxic activity upon human cancer cell lines in vitro and the undetected in vivo acute toxicity of these compounds.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antioxidantes/farmacología , Complejos de Coordinación/farmacología , Cobre/química , Curcumina/análogos & derivados , Magnesio/química , Manganeso/química , Zinc/química , Animales , Antineoplásicos Fitogénicos/síntesis química , Antioxidantes/síntesis química , Hidroxitolueno Butilado/farmacología , Cationes Bivalentes , Línea Celular Tumoral , Cisplatino/farmacología , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Curcumina/química , Células Epiteliales , Humanos , Concentración 50 Inhibidora , Ligandos , Peroxidación de Lípido/efectos de los fármacos , Células MCF-7 , Masculino , Ratones , Modelos Moleculares , Pruebas de Toxicidad Aguda , alfa-Tocoferol/farmacologíaRESUMEN
Synthesis of biaryl-containing macrocycles has been carried out through a four-step approach comprising two Ugi four component reactions and a Suzuki-Miyaura macrocyclization. This protocol allowed the synthesis of 12- and 14-membered macrocycles. Cytotoxic activity evaluation showed that some of the molecules were effective against leukemia, glioblastoma and lung cancer cell lines (IC50 = 4.0, 5.9 and 7.6, respectively).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Antineoplásicos/química , Compuestos de Bifenilo/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Compuestos Macrocíclicos/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The effect of the stereochemistry of the sulfur atom on 1 H chemical shifts of the diasteromeric pair of cyclic sulfites of 4-[methoxy(4-nitrophenyl)methyl]-5-phenyl-1,3,2-dioxathiolan-2-oxide was investigated. The complete 1 H and 13 C NMR spectral assignment was achieved by the use of one-dimensional and two-dimensional NMR techniques in combination with X-ray data. A correlation of experimental data with theoretical calculations of chemical shift tensors using density functional theory and topological theory of atoms in molecules was made. Copyright © 2016 John Wiley & Sons, Ltd.
RESUMEN
Curcumin and its derivatives have been extensively studied for their remarkable medicinal properties, and their chemical synthesis has been an important step in the optimization of well-controlled laboratory production. A family of new compounds that mimic the structure of curcumin and curcuminoids, here named retro-curcuminoids (7-14), was synthesized and characterized using 1D ¹H- and 13C-NMR, IR, and mass spectrometry; the X-ray structure of 7, 8, 9, 10, 12, 13, and 14 are reported here for the first time. The main structural feature of these compounds is the reverse linkage of the two aromatic moieties, where the acid chloride moiety is linked to the phenolic group while preserving α, ß-unsaturated ketone functionality. The cytotoxic screening of 7, 8, 9, and 10 at 50 and 10 µg/mL was carried out with human cancer cell lines K562, MCF-7, and SKLU-1. Lipid peroxidation on rat brain was also tested for compounds 7 and 10. Compounds 7, 8, and 10 showed relevant cytotoxic activity against these cancer cell lines, and 10 showed a protective effect against lipid peroxidation. The molecular resemblance to curcuminoids and analogs with ortho substituents suggests a potential source of useful bioactive compounds.
Asunto(s)
Antineoplásicos , Curcumina/análogos & derivados , Estirenos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ácidos Cumáricos/química , Cristalografía por Rayos X , Humanos , Células MCF-7 , Masculino , Resonancia Magnética Nuclear Biomolecular , Ratas , Ratas WistarRESUMEN
The new phenyl glycine derivative of perezone was obtained in a single reaction step in ca. 80% yield which showed remarkable cytotoxic activity against the astrocytoma U-251 cell line. After 24 h of exposure, both perezone (IC50 = 6.83 ± 1.64 µM) and its phenyl glycine derivative (2.60 ± 1.69 µM) showed cytotoxic effect on U-251 cells but were five times less cytotoxic on the non-tumoral SVGp12 cell line (IC50 = 28.54 ± 1.59 and 31.87 ± 1.54 µM respectively). Both compounds induced cellular morphological changes (pyknosis or cytoplasmic vacuolization) and increased the expression of caspases 3, 8, and 9 genes related to apoptosis. In the acute toxicity study, phenyl glycine perezone (DL50 = 2000 mg/Kg) demonstrated to be less toxic than perezone (DL50 = 500 mg/Kg). Phenylglycine-perezone can envisage a beneficial therapeutic potential.
RESUMEN
To our previously reported first crystal structure of a homoleptic zinc curcuminoid complex with square pyramidal geometry, we add herein three new geometries of homoleptic type complexes i.e. octahedral, trigonal-pyramidal, and trigonal-bipyramidal. Octahedral geometry was observed in the new pseudo-polymorph of the DAC-Zn complex resulting from crystallization in DMF, while square-pyramidal geometry was obtained in DMSO. Improving crystallinity involved suppressing the phenolic interactions by etherification and esterification. The complete characterization of these complexes was carried out using SCXRD, IR, MS, EA, liquid, and solid-state NMR. Moreover, the cytotoxic activity of all complexes was evaluated. The IC50 values for the DiMeOC-Zn (7) complex were 8 or 22 times higher than for cisplatin in the U251 and HCT-15 cell lines, indicating a high antiproliferative and therapeutic potential.
RESUMEN
Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Organometálicos/farmacología , Rutenio/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , ADN/metabolismo , Resistencia a Antineoplásicos , Humanos , Hidrólisis , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Ligandos , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Compuestos de Platino/farmacología , Rutenio/química , Rutenio/metabolismo , Relación Estructura-Actividad , Transferrina/metabolismoRESUMEN
Con el objetivo de evaluar la aplicación del Método Necesidades Básicas Insatisfechas (NBI) en la detección de comunidades con mayor riesgo de desnutrición en los primeros 6 años de vida, se realizó un estudio de prevalencia en la Parroquia Juan Villegas, Barquisimeto, Venezuela. De la población de niños del grupo de edad de la zona, se obtuvo una muestra aleatoria estratificada y por conglomerados; se constituyeron cinco gradientes de barrios según el porcentaje de hogares con NBI. Se evaluaron 538 niños en 16 barrios a través de indicadores de NBI en la familia, encuesta Graffar Méndez Castellano peso y talla. El 10.8 por ciento de la muestra presentó desnutrición actual, el 25.3 por ciento déficit talla/edad, y el 5.8 por ciento sobrepeso; el porcentaje de niños con déficit nutricional crónico fue mayor en los gradientes NBI con peores condiciones de vida, siendo 30 por ciento en los barrios con 60-100 por ciento NBI. La presencia de viviendas inapropiadas, sin algún servicio básico, bajo nivel educativo de la madre, ingresos familiares tipo donaciones, y residencia en barrios con 60-100 por ciento NBI se asoció con mayor riesgo de presentar déficit talla/edad (riesgo relativo estimado:1.55, 1.29, 1.35, 2.43 y 1.2 respectivamente). El riesgo de déficit peso/edad fue mayor en quienes habitan viviendas inadecuadas, cuando existe hacinamiento crítico ó jefe de familia obrero no especializado (riesgo relativo estimado: 1.56, 1.34 y 1.39 respectivamente). El método utilizado ofrece ventajas para identificar las localidades y familias con mayor riesgo de desnutrición infantil, a fin de establecer en ellos programas de intervención nutricional