Complexes of Pd(II) and Pt(II) with 9-aminoacridine: reactions with DNA and study of their antiproliferative activity

Four new metal complexes {M = Pd(II) or Pt(II)} containing the ligand 9-aminoacridine (9AA) were prepared. The compounds were characterized by FT-IR and 1H, 13C, and 195Pt NMR spectroscopies. Crystal structure of the palladium complex of formulae [Pd(9AA)(μ-Cl)]2 · 2DMF was determined by X-ray diffraction. Two 9-acridine molecules in the imine form bind symmetrically to the metal ions in a bidentate fashion through the imine nitrogen atom and the C(1) atom of the aminoacridine closing a new five-membered ring. By reaction with phosphine or pyridine, the Cl bridges broke and compounds with general formulae [Pd(9AA)Cl(L)] (where L = PPh3 or py) were formed. A mononuclear complex of platinum of formulae [Pt(9AA)Cl(DMSO)] was also obtained by direct reaction of 9-aminoacridine and the complex [PtCl2(DMSO)2]. The capacity of the compounds to modify the secondary and tertiary structures of DNA was evaluated by means of circular dichroism and electrophoretic mobility. Both palladium and platinum compounds proved active in the modification of both the secondary and tertiary DNA structures. AFM images showed noticeable modifications of the morphology of the plasmid pBR322 DNA by the compounds probably due to the intercalation of the complexes between base pairs of the DNA molecule. Finally, the palladium complex was tested for antiproliferative activity against three different human tumor cell lines. The results suggest that the palladium complex of formula [Pd(9AA)(μ-Cl)]2 has significant antiproliferative activity, although it is less active than cisplatin.

Photocontrolled DNA Binding of a Receptor-Targeted Organometallic Ruthenium(II) Complex

A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as"tumor-targeting devices" since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium-peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV-vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η6-p-cym)Ru(bpm)(H2O)]2+, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, 5′dCATGGCT and 5′dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide-oligonucleotide hybrid, Phac-His-Gly-Met-linker-p5′dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids.

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

La vida que quiero: proyectos de vida aplicando psicología positiva y metodologías visuales

Éxito y fracaso escolar conviven diariamente en la escuela. Uno es oportunidad parael otro y viceversa. Combinando la teoría de las fortalezas del carácter, identidad narrativa,teoría de la autodeterminación y otros constructos con metodologías audiovisuales, el programainvita a jóvenes a descubrir sus recursos personales y reescribir su biografía a partir deellos, de modo de finalmente proyectarlos hacia el futuro en un Proyecto de Vida positivo yrealista. Para lograrlo, los alumnos son invitados a auto-observarse, observar a sus compañerosy a entrevistar a sus familiares, aprovechando siempre las representaciones visuales. Estanueva versión de la propia vida queda plasmada en un relato digital, una secuencia de imágenesque retrata la propia vida pasada, presente y futura, sincronizada con un guion que dacuenta del proceso de convertirse en Persona con Fortalezas del Carácter. Se discuten las dificultades,las oportunidades y los desafíos de su implementación en escuelas en Barcelona,Castelldefels y Viladecans.

Bienestar en universitarios: de las perspectivas teóricas a un estudio exploratorio

Este trabajo es un resumen de las principales aportaciones teóricas de los autoresde la Psicología Positiva al estudio del bienestar, del optimismo y la felicidad de las personas,tanto niños, adolescentes, jóvenes como adultos. Se examinan los principales tipos de bienestary sus elementos y características, así como se hace un repaso de los principales autores einvestigaciones al respecto de este campo de estudio. A continuación se muestran los principalesresultados de una investigación sobre fortalezas de carácter y bienestar en una muestra deestudiantes de maestro, mediante la aplicación de un cuestionario online sobre virtudes y fortalezasde carácter y otro de bienestar y malestar psicológico y su posterior cálculo estadísticodescriptivo y correlacional. Finalmente se concluye con posibles implicaciones de estos resultados en su formación universitaria y posterior desarrollo profesional como maestros.

Bienestar en universitarios: de las perspectivas teóricas a un estudio exploratorio

Este trabajo es un resumen de las principales aportaciones teóricas de los autoresde la Psicología Positiva al estudio del bienestar, del optimismo y la felicidad de las personas,tanto niños, adolescentes, jóvenes como adultos. Se examinan los principales tipos de bienestary sus elementos y características, así como se hace un repaso de los principales autores einvestigaciones al respecto de este campo de estudio. A continuación se muestran los principalesresultados de una investigación sobre fortalezas de carácter y bienestar en una muestra deestudiantes de maestro, mediante la aplicación de un cuestionario online sobre virtudes y fortalezasde carácter y otro de bienestar y malestar psicológico y su posterior cálculo estadísticodescriptivo y correlacional. Finalmente se concluye con posibles implicaciones de estos resultados en su formación universitaria y posterior desarrollo profesional como maestros.