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Carbosilane ruthenium(ii) dendrimers have been complexed with conventional anti-cancer drugs. Due to its features, the presence of ruthenium within a dendrimer structure improves the anti-cancer properties of nanocomplexes containing 5-flurouracyl, methotrexate and doxorubicin. These dendrimers could be promising carriers of anti-cancer medicines. Ruthenium dendrimers that are positively charged can also enhance the cytotoxicity to cancer cells; moreover, they can form stable complexes with drugs. Results indicate that ruthenium dendrimers combined with doxorubicin and methotrexate significantly reduced the viability of leukaemia 1301 and HL-60 cancer cells.

La pandemia de enfermedad por coronavirus 2019 (COVID-19) ha incidido de forma negativa en los programas de rehabilitación cardiaca (PRC) españoles.Este trabajo tiene como objetivo fundamental el analizar la posibilidad de mantenerlos abiertos y como secundario valorar si se mantienen los beneficios demostrados a nivel físico y psicológico.Analizamos los resultados de nuestro PRC en el año 2020 (119 pacientes) y los comparamos con los del año 2019 (121 pacientes), libre de COVID-19. Se comparan distintas variables generales, y los resultados obtenidos en capacidad física, a nivel psicológico, así como las complicaciones y abandonos.No existen diferencias significativas entre ambos grupos en la edad (61.6 vs. 61.5), sexo (mujeres: 12.6 vs. 14.8%), diagnóstico de cardiopatía isquémica (106 vs. 99) y fracción de eyección de ventrículo izquierdo (55.9 vs. 55.8%). La ansiedad media-alta fue superior al inicio (p = 0.02) y final (p = 0.002) del programa en el año 2019, así como las puntuaciones del patrón de conducta tipo A (p = 0.041 vs. 0.034). El porcentaje de depresión fue similar. Más del 95% de los pacientes del año 2020 referían miedo al contagio. La capacidad funcional aumentó, pero menos en el año 2020 (p = 0.001). La duración del programa fue superior en el año 2020 (p = 0.001). Los abandonos (15 vs. 11 pacientes) no mostraron diferencias significativas.Los PRC en época COVID-19 son posibles y siguen mostrando beneficios. La duración del programa fue mayor por periodos de falta de asistencia. La menor capacidad física puede estar relacionada con el uso de la mascarilla.COVID-19 pandemic has had a negative impact on Spanish Cardiac Rehabilitation Programmes (CRP).The main objective of this study is to analyze the possibility of keeping these units open and, secondly, to assess whether demonstrated physical and psychological benefits are preserved.We analyzed results of our CRP in 2020 (119 patients) and compared them with those of 2019 (121 patients), year free of Covid. We compare different general variables, and results obtained in physical capacity, psychological level, as well as complications and dropouts.There were no significant differences between two groups in age (61.6 vs. 61.5), sex (women: 12.6% vs. 14.8%), diagnosis of ischemic heart disease (106 vs. 99) and left ventricular ejection fraction (55.9% vs. 55.8%). Mean-high anxiety was higher at baseline (p = 0.02) and endline (p = 0.002) of program in 2019, as well as type A behavior pattern scores (p=0.041 and 0.034). Percentage of depression was similar. More than 95% of patients in 2020 reported fear of infection. Functional capacity increased, but less in 2020 (p = 0.001). Programme duration was longer in 2020 (p=0.001). Dropouts (15 vs. 11 patients) showed no significant differences.CR programmes in COVID-19 era are possible and continue to show benefits. The duration of programme was longer due to periods of non-attendance. Lower physical capacity may be related to mask use.

Analizar los efectos de un programa de rehabilitacion cardiaca (PRC) en pacientes portadores de desfibrilador automatico implantable (DAI), a nivel de calidad de vida y de actividad sexual. Metodo: Se incluyeron 25 pacientes (22 hombres y 3 mujeres). Se estudiaron la existencia de descargas del desfibrilador y su repercusion sobre la pareja, asi como los efectos del PRC a nivel fisico, psicologico y en la esfera sexual. Resultados: La edad media de los enfermos fue de 55 anos (22 a 79). Al inicio, el miedo a las descargas del dispositivo estaba presente en todos los enfermos. A su llegada, 14 pacientes (56%) no habian tenido actividad sexual: 2 con edades de 69 y 79 anos; una mujer por ansiedad severa, un hombre alcoholico, y 10 por haber transcurrido menos de un mes desde el implante. Nueve hombres y dos mujeres la habian reiniciado: 5 a los 5-52 meses del implante y 6 a los 30 dias de hacerse implantado el DAI, mientras realizaban el PRC. Al finalizar, 21 pacientes habian reiniciado la actividad sexual. Dos hombres presentaron signos clinicos de depresion y ansiedad, uno de ellos preciso tratamiento especializado. La capacidad funcional mejoro de forma significativa: 6,5 ± 3,0 MET al inicio del programa y 9,2 ± 3,3 MET al final, con p < 0,005. Hubo una sola descarga inapropiada. Conclusiones: Las descargas con los nuevos dispositivos han descendido significativamente. Por este motivo, y con las acciones de los PRC a nivel fisico, psicologico e informativo, se consigue controlar las disfunciones en calidad de vida y sexualidad

Ruthenium belongs to the family of metals widely used in anticancer therapy (platinum, arsenic, antimony, bismuth, gold, vanadium, iron, rhodium, titanium, gallium). This paper deals with a new kind of ruthenium terminated carbosilane dendrimers (CRD), consisting of carbosilane dendrons functionalized with N-, NH 2 -donor monodentate and N,N-chelating ruthenium complexes. The biophysical characterization, hemolytic activity and the cytotoxicity towards cancer (HL-60) and normal (B-14) cell lines of CRDs have been determined. The data indicate that: (1) generation 0 metallodendrimers are the most effective drugs, being non-toxic for normal cells but induced significant cytotoxicity (>90%) in cancer cells; (2) an increase of generation leads both increased cytotoxicity of CRDs and the levelling of the difference in their action on normal and cancer cells; (3) coordination modes of ruthenium in a dendrimer scaffold did not correlate with their cytotoxicity towards normal and cancer cells. Results suggest that ruthenium dendrimers can be considered as alternative anticancer therapeutic agent.

Metallodendrimers&mdash, dendrimers with included metals&mdash, are widely investigated as biocompatible equivalents to metal nanoparticles. Applications can be expected in the fields of catalysis, as chemical sensors in molecular recognition and as anticancer drugs. Metallodendrimers can also mimic certain biomolecules, for example, haemoprotein in the case of using a dendrimer with a porphyrin core. In previous papers, we showed the promising anticancer effects of carbosilane ruthenium dendrimers. The present paper is devoted to studying biocompatibility and the cytotoxic effect on normal and cancer cells of carbosilane ruthenium dendrimers labelled with fluorescent probe fluorescein isothiocyanate (FITC). The addition of fluorescent probe allowed tracking the metallodendrimer in both normal and cancer cells. It was found that carbosilane ruthenium dendrimer labelled with FITC in concentration up to 10 &micro, mol/L was more cytotoxic for cancer cells than for normal cells. Thus, FITC labelled carbosilane ruthenium dendrimer is a good candidate for diagnostic imaging and studying anticancer effects of metallodendrimers in cancer therapy.

Coordination of ruthenium arene fragments on carbosilane dendrimers' surface greatly increases their antitumor properties. Newly synthetized ruthenium dendrimers are water-soluble, monodisperse and stable. Since carbosilane dendrimers are good carriers of drugs and genes, the presence of ruthenium in their structure makes them promising candidates for new drug delivery systems with improved antitumor potential. Carbosilane ruthenium dendrimers are more toxic to cancer cells than normal cells. Results of several

We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.

A family of heterofunctional Schiff base carbosilane metallodendrons with [Ru(η 5 -C5H5)(PTA)Cl] (PTA=1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane) at the focal point and dimethylamino groups on the periphery are described. The new systems have proved their ability to interact with biological molecules such as Human Serum Albumin (HSA) without affecting its secondary structure and erythrocytes membranes, causing haemolysis in a dose and generation dependent way. The combination of two active functional groups in one single dendritic platform has shown a cooperative effect in the viability of HeLa and PC-3 cells, with the second generation derivative standing out as the most promising with the lowest IC50. Experiments focused on advanced prostate cancer have shown an antimetastasic activity for those metallodendrons, hindering the adhesion of cells in one of the main targets of metastasis, bones, and inhibiting cell migration. Finally, the second generation metallodendron with one single metal centre and four dimethylamino groups on the dendritic wedge, was selected for an ex vivo experiment in nude mice with advanced prostate cancer inhibiting the tumour growth in a 40% compared to control mice.

Background Prostate cancer is the fifth cause of death among men worldwide. Patients suffering resistant prostate tumor, unresponsive to common treatments, can only be treated with palliative therapy. Materials and methods Ruthenium(II) carbosilane metallodendrimers containing arene moieties were evaluated as a novel antitumor nanotherapy against resistant prostate cancer. The preclinical evaluation included relevant in vitro, ex vivo and in vivo assays, in an experimental mice model of human prostate cancer. Results Promising cytotoxic, antiproliferative and antimetastatic behaviors were observed. After treatment with these nanocompounds, mice underwent a significant reduction of tumor volume, in comparison to non-treated animals. Conclusions The selective antitumor behavior and the lack of toxicity, potentially make ruthenium(II) metallodendrimers promising agents for cancer therapy.

Carbosilane dendrimers containing vanillin on the surface have been prepared with the purpose of combining the unique antioxidant and anticancer properties of polyphenols and dendrimers. These new compounds exhibit antioxidant potency as free-radical scavengers, as determined by DPPH and ABTS. Remarkably, all synthesized dendrimers exhibit improved antioxidant efficacy compared to vanillin. Anticancer activity has been studied against HeLa cervical and PC3 human prostate cancer cell lines. Proliferation, cell cycle, adhesion and migration in human prostate tumor cells have been studied. Data revealed a general trend indicating that polyphenolic dendrimers are more cytotoxic than their monopolyphenolic counterparts in both cancer cell lines.

A series of new organometallic carbosilane dendrimers (first and second generation) and the corresponding non-dendritic mononuclear based on ruthenium arene fragments are described. The metallodendrimers were prepared by reactions of the precursor [Ru(η(6)-p-cymene)Cl2]2 with carbosilane dendrimers functionalized with N-donor monodentate ligands such as NH2- and pyridine, or with N,O-, N,N-chelating imine ligands. While the dendrimer precursors are insoluble in DMSO or water, novel metallodendrimers are soluble in DMSO and some of them are even highly soluble in water. The molecular structure of the "Ru-NH2" mononuclear compound (zero generation) was determined by single-crystal X-ray crystallography. The cytotoxicity activity of these dendritic structures was evaluated in several human cancer cell lines and compared with that of the corresponding mononuclear ruthenium complexes. Most compounds display significant cytotoxic activities in the low micromolar range with the first generation ruthenium dendrimers being the most active compounds. The cell death type for selected compounds has been studied as well as their reactivity towards relevant biomolecules such as DNA, Human Serum Albumin (HSA) and Cathepsin-B. All the data point to a mode of action different from that of cisplatin for most complexes. First generation ruthenium dendrimers inhibit Cathepsin-B, which may suggest potential antimetastatic properties of these compounds.

A series of new organometallic carbosilane dendrimers functionalized with Copper(II) complex on the surface were synthesized and characterized as potential anticancer agents. These metallodendrimers were synthesized through the reaction of dendritic ligands containing N,N- and N,O- donor atoms able to act as chelating agents with CuCl2 as metallic ion precursor. The structural characterization of these complexes was addressed through the use of different analytical and spectroscopical techniques. Particularly, an electron paramagnetic resonance study was performed to corroborate the coordination properties of these dendritic ligands. A preliminary study was carried out to establish the cytotoxicity of the new synthesized compounds in human prostate (PC3) and human cervical (HeLa) cancer cell lines in order to evaluate their potential as anticancer agents and compare their activity with other copper or analogous ruthenium metallodendrimers.

Alpha-melanotropin, Ac-Ser(1)-Tyr-Ser-Met-Glu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2)(1), is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of alphaMSH, including a broadly used and more potent the NDP-alphaMSH peptide, Ac-Ser(1)-Tyr-Ser-Nle(4)-Glu-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2), are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-alphaMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand alphaMSH, are exemplified by compound 7, Ac-Ser(1)-Tyr-Ser-Met-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2) (Oic: octahydroindole-2-COOH, 4,4'-Bip: 4,4'-biphenylalanine, Pip: pipecolic acid), shortly NODBP-alphaMSH, which has an IC(50)=0.74 nM (binding assay) and EC(50)=0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-alphaMSH: Ac-Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9) -NH(2) (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8) segment was found to be critical for high agonist potency, while the C-terminal Trp(9) residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.

Melanocortin receptors (MC1-5R) and their endogenous ligands (melanocyte-stimulating hormones and adrenocorticotropic hormone) are involved in many physiological processes in humans. Of those receptors, the actions of MC5R are the least understood despite its broad presence in the numerous peripheral tissues and brain. In this study, we describe synthesis and pharmacological properties in vitro (receptor-binding affinity and agonist activity) of several cyclic analogs of alphaMSH which are potent agonists at hMC5R (EC(50) below 1 nM) and of enhanced receptor subtype selectivity (more than 2000-fold versus hMC1b,3R and about 70- to 200-fold versus hMC4R). These compounds are analogs of Ac-Nle(4)-cyclo[Asp(5)-His(6)-D-Nal(2')(7)-Pip(8)-Trp(9)-Lys(10)]-NH(2) (Pip: pipecolic acid) in which His(6) has been replaced with sterically hindered amino acids. They may be useful tools in the elucidation of the MC5R role in skin disorders and in immunomodulatory and in anti-inflammatory actions of alphaMSH.

The physiological role of melanocortin receptor 5 (MC5R) in humans is not clear despite its broad presence in various peripheral sites and in the brain, cortex, and cerebellum. To differentiate between functions of this receptor and those of the other melanocortin receptors (hMC1,3,4R), peptides with improved receptor subtype selectivity are needed. The endogenous ligands, melanocortins, and their various synthetic analogues are not particularly selective for hMC5R. In this study, cyclic peptides derived from MTII, Ac-Nle-cyclo(Asp-His6-D-Phe7-Arg8-Trp-Lys)-NH2 (a pan-agonist at the melanocortin receptors) were prepared and tested in binding and functional assays on CHO cells expressing hMC1b,3-5R. The analogues included in their structures sterically constrained hydrophobic amino acids in positions 6 (His) and 8 (Arg), and the D-4,4'-biphenyl residue in position 7 (D-Phe). Several of the new compounds were selective potent agonists at hMC5R. They are exemplified by peptide 29, Ac-Nle-cyclo(Asp-Oic6-D-4,4'-Bip7-Pip8-Trp-Lys)-NH2 (Oic=octahydroindole-2-COOH; 4,4'-Bip=4,4'-biphenylalanine; Pip=pipecolic acid) of IC50=0.95 nM and EC50=0.99 nM at hMC5R and selectivity for this receptor with respect to the other melanocortin receptors greater than 5000-fold.

coordinado por Daniel Brinks, Marcelo Leiras y Scott Mainwaring (2014), se presenta como una obra que tiene por objeto avanzar en la agenda de investigacion sobre democratizacion, a partir del legado de Guillermo O’Donnell. Los capitulos que conforman este texto se organizan basandose en tres temas centrales en la trayectoria academica del fallecido politologo argentino: los cambios de regimenes (rupturas del regimen democratico y transiciones hacia la democracia); la economia politica de las nuevas democracias; y la naturaleza y calidad del regimen democratico que resulta de las transiciones democraticas de la tercera ola. Cabe destacar que dicha estructura, ademas de brindarle dinamismo y coherencia sustantiva al contenido del libro como un todo, refleja el desarrollo intelectual y la labor academica de O’Donnell, en estrechisima relacion con el devenir politico historico de los paises de America del Sur. A continuacion se presentaran los principales argumentos y contribuciones que se realizan en los capitulos que componen la obra, para luego senalar algunos comentarios criticos e interrogantes que surgen de la lectura del mismo.Los primeros tres capitulos se abocan al estudio de los cambios de regimenes segun los aportes hechos por O’Donnell en sus obras

The NS1 protein is a nonstructural protein encoded by the influenza A virus. It is responsible for many alterations produced in the cellular metabolism upon infection by the virus and for modulation of virus virulence. The NS1 protein is able to perform a large variety of functions due to its ability to bind various types of RNA molecules, from both viral and nonviral origin, and to interact with several cell factors. With the aim of exploring whether the binding of NS1 protein to viral RNA (vRNA) could constitute a novel target for the search of anti-influenza drugs, a filter-binding assay measuring the specific interaction between the recombinant His-NS1 protein from influenza A virus and a radiolabeled model vRNA ( 32 P-vNSZ) was adapted to a format suitable for screening and easy automation. Flashplate ® technology (PerkinElmer, Waltham, MA), either in 96- or 384-well plates, was used. The Flashplate ® wells were precoated with the recombinant His-NS1 protein, and the binding of His-NS1 to a 35 S-vNSZ probe was measured. A pilot screening of a collection of 27,520 mixtures of synthetic chemical compounds was run for inhibitors of NS1 binding to vRNA. We found 3 compounds in which the inhibition of NS1 binding to vRNA, observed at submicromolar concentrations, was correlated with a reduction of the cytopathic effect during the infection of cell cultures with influenza virus. These results support the hypothesis that the binding of NS1 to vRNA could be a novel target for the development of anti-influenza drugs. (Journal of Biomolecular Screening 2008:581-590)

α-Melanotropin (αMSH), Ac-Ser 1 -Tyr 2 -Ser 3 -Met 4 -Glu 5 -His 6 -Phe 7 -Arg 8 -Trp 9 -Gly 10 -Lys 11 -Pro 12 -Val 13 -NH 2 , 1 has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of αMSH were studied. These ligands were analogs of MTII, Ac-Nle 4 -cyclo-(Asp 5 -His 6 - d -Phe 7 -Arg 8 -Trp 9 -Lys 10 )-NH 2 , a potent pan-agonist at the human melanocortin receptors (hMC1,3–5R). In the structure of MTII, the His 6 -D-Phe 7 -Arg 8 -Trp 9 segment has been recognized as “essential” for molecular recognition at the human melanocortin receptors (hMC1,3–5R). Herein, the role of the Trp 9 in the ligand interactions with the hMC1b,3–5R has been reevaluated. Analogs with various amino acids in place of Trp 9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3–5R). Several of the new peptides were high potency agonists (partial) at hMC1bR (EC 50 from 0.5 to 20 nM) and largely inactive at hMC3–5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.

alpha-Melanocyte stimulating hormone (alphaMSH), Ac-Ser(1)-Tyr(2)-Ser(3)-Met(4)-Glu(5)-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2), is an endogenous agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with alphaMSH and its synthetic analog NDP-alphaMSH, Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH(2), have been previously proposed. In those models, the 6-9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp(9) of NDP-alphaMSH in interactions with hMC1bR. Analogs of NDP-alphaMSH with various amino acids in place of Trp(9) were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high agonist potency at hMC1bR (EC(50) = 0.5-5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp(9) residue of NDP-alphaMSH was determined to be not essential for molecular recognition at hMC1bR.

SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.