A convenient synthesis of new 6-substituted purinylcarbanucleosides on cyclopenta[b]thiophene

The 12th International Electronic Conference on Synthetic Organic Chemistry session Bioorganic Chemistry and Natural ProductsThe first members of a new family of heterocarbobicyclic nucleoside analogues have been synthesized from the cis/trans mixture of (4-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)methanols cis/trans-7. The separation of cis and trans intermediates during preparation of the 6-chloropurine derivatives allowed separate preparation of the purine heterocarbanucleosides cis-10 and trans-11, from which cis-(12-14) and trans-(16-18) were obtained by replacement of the 6-chloro substituent with amino, hydroxy and cyclopropylamino groups. Additionally, the 6-phenyl-purinyl analogues cis-15 and trans-19 were prepared from cis-10 and trans-11 using Suzuki-Miyaura methodologyThe authors thank the Xunta de Galicia for financial support under project PGIDIT02BTF20305P

A ‘click chemistry’ approach to the straightforward synthesis of new 4-aryl-1,2,3-triazolocarbanucleosides

The synthesis and biological evaluation as antiviral agents of a series of racemic 4-aryl-1,2,3- triazolyl carbanucleosides of type (±)-10/(±)-11 related to the broad spectrum antiviral agent ribavirin 1 are described. These compounds were produced using a “click chemistry” strategy starting from readily available protected alcohol 13b. The synthetic approach made use of olefinbased organic reactions for the stereoselective construction of the appropriately functionalized cyclopentane ring moiety followed by copper (I) catalyzed Huisgen 1,3-dipolar cycloaddition of azides and alkynes for the regioselective construction of the heterocyclic triazole moietyThe authors thank the Xunta de Galicia for financial support of this work under Project PGIDT02BTF20305PR. M.D.G. thanks the Xunta de Galicia for financial support under “Programa Isidro Parga Pondal”S

Synthesis and Antiviral Activities of Novel Purinyl- and Pyrimidinylcarbanucleosides Derived from Indan

The 12th International Electronic Conference on Synthetic Organic Chemistry session Bioorganic Chemistry and Natural ProductsStarting from (±)-trans- and (±)-cis-3-hydroxymethyl-1-indanol, novel 6-substituted purinylcarbanucleoside derivatives of indan (5, 6, 9, 10, 15 and 17) were synthesized through a key coupling reaction with 6-chloropurine under Mitsunobu conditions. Suzuki–Miyaura reactions of the protected 6-chloropurine derivative with different arylboronic acids afforded the corresponding 6-arylpurinylcarbanucleoside derivatives. Finally, three new 5-halouracilcarbanucleosides (19, 20 and 21) were prepared by reaction of uracilcarbanucleoside 18 with different N-halosuccinimides. All of the new analogues were evaluated for antiviral activity against a wide variety of virusesThe authors thank the Xunta de Galicia for financial support of this work under projects PGIDT05PXIB20301PR and 07CSA008203P

Perturbation theory/machine learning model of ChEMBL data for dopamine targets: docking, synthesis, and assay of new l-prolyl-l-leucyl-glycinamide peptidomimetics

[Abstract] Predicting drug–protein interactions (DPIs) for target proteins involved in dopamine pathways is a very important goal in medicinal chemistry. We can tackle this problem using Molecular Docking or Machine Learning (ML) models for one specific protein. Unfortunately, these models fail to account for large and complex big data sets of preclinical assays reported in public databases. This includes multiple conditions of assays, such as different experimental parameters, biological assays, target proteins, cell lines, organism of the target, or organism of assay. On the other hand, perturbation theory (PT) models allow us to predict the properties of a query compound or molecular system in experimental assays with multiple boundary conditions based on a previously known case of reference. In this work, we report the first PTML (PT + ML) study of a large ChEMBL data set of preclinical assays of compounds targeting dopamine pathway proteins. The best PTML model found predicts 50000 cases with accuracy of 70–91% in training and external validation series. We also compared the linear PTML model with alternative PTML models trained with multiple nonlinear methods (artificial neural network (ANN), Random Forest, Deep Learning, etc.). Some of the nonlinear methods outperform the linear model but at the cost of a notable increment of the complexity of the model. We illustrated the practical use of the new model with a proof-of-concept theoretical–experimental study. We reported for the first time the organic synthesis, chemical characterization, and pharmacological assay of a new series of l-prolyl-l-leucyl-glycinamide (PLG) peptidomimetic compounds. In addition, we performed a molecular docking study for some of these compounds with the software Vina AutoDock. The work ends with a PTML model predictive study of the outcomes of the new compounds in a large number of assays. Therefore, this study offers a new computational methodology for predicting the outcome for any compound in new assays. This PTML method focuses on the prediction with a simple linear model of multiple pharmacological parameters (IC50, EC50, Ki, etc.) for compounds in assays involving different cell lines used, organisms of the protein target, or organism of assay for proteins in the dopamine pathway.Ministerio de Economía y Competitividad; CTQ2016-74881-PGobierno Vasco; IT1045-16Xunta de Galicia; GPC2014/003Xunta de Galicia; CN 2012/069Xunta de Galicia; ED431D 2017/16Xunta de Galicia; ED431D 2017/23Xunta de Galicia; GRC2014/049Xunta de Galicia; ED431D 2017/2

Prediction of multi-target networks of neuroprotective compounds with entropy indices and synthesis, assay, and theoretical study of new asymmetric 1,2-rasagiline carbamates

In a multi-target complex network, the links (Lij) represent the interactions between the drug (di) and the target (tj), characterized by different experimental measures (Ki, Km, IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (cj). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%–90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular OPEN ACCESS Int. J. Mol. Sci. 2014, 15 17036 targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentallyThe authors thank the Xunta de Galicia for financial support of this work under project 07CSA008203PRS

La imagen y la narrativa como herramientas para el abordaje psicosocial en escenarios de violencia. Departamentos del Cesar, Norte de Santander y Cauca

El presente trabajo expone la importancia de la violencia efectuada por grupos victimarios al margen de la ley y el ejército, que generaron actos de violencia hacia la población, provocando una crisis humanitaria, desplazamientos forzados, muerte de la población civil y la violación de los derechos humanos. Causando daños psicológicos, emocional y de salud mental en las personas. El caso Peñas Coloradas, deja conocer una comunidad organizada y pujante que se formó de la nada, del deseo de huir del hambre y la violencia, crearon el caserío de Peñas Coloradas a orillas del rio Caguán, donde no existía la presencia del estado, pero había reglas y las respetaban. El abandono del estado creo condiciones precarias en la población, la economía de las familias se dificulto y provoco que la comunidad tomara la siembra y procesamiento de la coca para mejorar su económica, lo que trajo desgracia, fue el motivo para que el estado se fijara en ellos, como auxiliadores del terrorismo y el ejército fijara a Peñas Coloradas como un campamento de la Guerrilla. El 25 de abril del 2004, el caserío fue invadido y destruido por el ejército, reseñando y amenazo a los habitantes diciendo” Nosotros llegamos mansitos, los de atrás vienen con las motosierras” lo que genero temor en los habitantes y decidieron desplazarse, hacia Cartagena del Chaira, Caquetá, generándoles hambre y miseria. El caso Ana Ligia, deja ver la valentía de una mujer por querer ayudar a una comunidad víctima del conflicto, siendo ella misma víctima de ese conflicto, al ser desplazada con sus hijos de su pueblo Aquitania en dos oportunidades en los años 2003 y 2004, no solo sufriendo el flagelo del desplazamiento si no también el no reconocimiento de sus derechos al ser despedida de su trabajo estando en estado de embarazo. Esta mujer deja ver un gran sentido de solidaridad y empatía con la comunidad desplazada, formándose como líder al trabajar con las víctimas de San Francisco. Así mismo refleja una situación de desempleo que no es ajena a muchas personas, las cuales a pesar de prepararse académicamente no logran un empleo fijo.This paper exposes the importance of violence carried out by perpetrators on the fringes of the law and the army, which generated acts of violence against the population, causing a humanitarian crisis, forced displacement, death of the civilian population and the violation of rights humans. Causing psychological, emotional and mental health damage in people. The Peñas Coloradas case reveals an organized and thriving community that was formed from nothing, from the desire to flee from hunger and violence, they created the village of Peñas Coloradas on the banks of the Caguán River, where there was no state presence, but there were rules and they respected them. The abandonment of the state created precarious conditions in the population, the families' economy became difficult and caused the community to take over the planting and processing of coca to improve their economy, which brought misfortune, was the reason for the state to fixate in them, as assistants to terrorism and the army established Peñas Coloradas as a Guerrilla camp. On April 25, 2004, the village was invaded and destroyed by the army, reviewing and threatening the inhabitants saying "We arrived small, the ones from behind come with the chainsaws" which generated fear in the inhabitants and they decided to move to Cartagena del Chaira, Caquetá, generating hunger and misery. The Ana Ligia case reveals the courage of a woman for wanting to help a community victim of the conflict, being herself a victim of that conflict, when she was displaced with her children from her Aquitania town on two occasions in 2003 and 2004, not only suffering the scourge of displacement, but also the non-recognition of their rights when being fired from their job while pregnant. This woman shows a great sense of solidarity and empathy with the displaced community, training as a leader by working with the victims of San Francisco. It also reflects a situation of unemployment that is not alien to many people, who despite preparing academically do not achieve a permanent job

Superiority of a Novel Multifunctional Amorphous Hydrogel Containing Olea europaea Leaf Extract (EHO-85) for the Treatment of Skin Ulcers: A Randomized, Active-Controlled Clinical Trial

This 8-week, multicenter, randomized, active-controlled, observer-blinded clinical trial was designed to demonstrate the accelerating effect on wound healing of the novel Olea europaea leaf extract hydrogel (EHO-85) by comparing it to a widely used amorphous hydrogel. Results showed that EHO-85 significantly accelerated wound healing, regardless of ulcer etiology (pressure, venous leg or diabetic foot) and prognosis, doubling the median wound area reduction compared with a reference amorphous hydrogel (79.4% vs. 39.7%; difference: −39.7%, 95% CI: −71.1 to −21.3%; p < 0.001). The intention-to-treat analysis was conducted on 195 patients from 23 Spanish health centers/nursing homes. This novel treatment balances the ulcer microenvironment by modulating reactive oxygen species and pH. These actions complement the moistening and barrier functions inherent to amorphous hydrogels, whilst also conferring EHO-85 its documented granulation formation and pain relief properties. Furthermore, efficacy was achieved safely and in a cost-efficient manner due to its multi-dose format, which reduced the amount of product needed by 85.8% over 8 weeks compared to single-use hydrogel. The present randomized controlled trial is a relevant milestone in evidence-based practice for being the first to demonstrate (i) the effectiveness of an amorphous hydrogel in accelerating wound healing and (ii) the superiority of a specific hydrogel over another.This research was funded by QUESPER R&D (Córdoba, Spain) and partially by the programme for the Reinforcement of Research Activity in the Clinical Management Units of the Andalusian Health Service (Department of Health. Regional Government of Andalusia, Spain)

Specific micronutrient concentrations are associated with inflammatory cytokines in a rural population of Mexican women with a high prevalence of obesity

It has been recognised recently that obese individuals have lower concentrations of micronutrients and this may affect the concentrations of inflammatory cytokines. A cross-sectional study was carried out to evaluate the association of specific micronutrients' status with chronic inflammation caused by obesity in 280 women (36·1 (sd 7·5) years) from seven rural communities in Mexico. Measurements of weight, height and waist circumference were made on all women and body composition was determined by dual-energy X-ray absorptiometry. Concentrations of the cytokines IL-1, TNF-α, IL-6, IL-10 and IL-12, lipid profile, and the micronutrients Zn and vitamins A, C and E were determined in fasting blood samples. Ordered logistic regression models were used to determine associations between categorised cytokine levels and micronutrients. It was found that 80 % of women were overweight or obese, and had significantly higher concentrations of C-reactive protein than normal-weight women (P = 0·05). The risk of higher levels of TNF-α, IL-6, IL-10 and IL-12 was reduced significantly among women with higher Zn concentrations (OR 0·63, 95 % CI 0·42, 0·96, P = 0·03; OR 0·57, 95 % CI 0·39, 0·86, P = 0·025; OR 0·63, 95 % CI 0·41, 0·96, P = 0·04; OR 0·62, 95 % CI 0·41, 0·95, P = 0·03, respectively). Higher concentrations of vitamin A were slightly associated with reduced risks of higher levels of IL-1 and IL-12 (OR 0·97, 95 % CI 0·95, 0·99, P = 0·03; OR 0·97, 95 % CI 0·94, 0·99, P = 0·03, respectively); when adjusting for BMI, this association was lost. No associations were found between vitamin C or vitamin E:lipids concentrations and inflammatory cytokines. In conclusion, higher Zn concentrations are associated with reduced risks of higher concentration of inflammation markers in a population of women with a high prevalence of obesity

Differences in the Clinical Profile and Management of Atrial Fibrillation According to Gender. Results of the REgistro GallEgo Intercéntrico de Fibrilación Auricular (REGUEIFA) Trial

[Abstract] To analyze the clinical profile and therapeutic strategy in atrial fibrillation (AF) according to gender in a contemporaneous patient cohort a prospective, multicenter observational study was performed on consecutive patients diagnosed with AF and assessed by cardiology units in the region of Galicia (Spain). A total of 1007 patients were included, of which 32.3% were women. The mean age of the women was significantly greater than that of the men (71.6 versus 65.7 years; p < 0.001), with a higher prevalence of hypertension (HTN) and valve disease. Women more often reported symptoms related to arrhythmia (28.2% in EHRA class I versus 36.4% in men), with a poorer level of symptoms (EHRA classes IIb and III). Thromboembolic risk was significantly higher among women (CHA2DS2-VASc 3 ± 1.3 versus 2 ± 1.5), in the same way as bleeding risk (HAS-BLED 0.83 ± 0.78 versus 0.64 ± 0.78) (p < 0.001), and women more often received anticoagulation therapy (94.1% versus 87.6%; p = 0.001). Rhythm control strategies proved significantly less frequent in women (55.8% versus 66.6%; p = 0.001), with a lesser electrical cardioversion (ECV) rate (18.4% versus 27.3%; p = 0.002). Perceived health status was poorer in women. Women were older and presented greater comorbidity than men, with a greater thromboembolic and bleeding risk. Likewise, rhythm control strategies were less frequent than in men, despite the fact that women had poorer perceived quality of life and were more symptomatic