Design of Two New Sulfur Derivatives of Perezone: In Silico Study Simulation Targeting PARP-1 and In Vitro Study Validation Using Cancer Cell Lines.

Poly-ADP-Ribose Polymerase (PARP-1) is an overexpressed enzyme in several carcinomas; consequently, the design of PARP-1 inhibitors has acquired special attention. Hence, in the present study, three compounds (8-10) were produced through a Michael addition protocol, using phenylmethanethiol, 5-fluoro-2-mercaptobenzyl alcohol, and 4-mercaptophenylacetic acid, respectively, as nucleophiles and perezone as the substrate, expecting them to be convenient candidates that inhibit PARP-1. It is convenient to note that in the first stage of the whole study, the molecular dynamics (MD) simulations and the quantum chemistry studies of four secondary metabolites, i.e., perezone (1), perezone angelate (2), hydroxyperezone (3), and hydroxyperezone monoangelate (4), were performed, to investigate their interactions in the active site of PARP-1. Complementarily, a docking study of a set of eleven sulfur derivatives of perezone (5-15) was projected to explore novel compounds, with remarkable affinity to PARP-1. The molecules 8-10 provided the most adequate results; therefore, they were evaluated in vitro to determine their activity towards PARP-1, with 9 having the best IC50 (0.317 µM) value. Additionally, theoretical calculations were carried out using the density functional theory (DFT) with the hybrid method B3LYP with a set of base functions 6-311++G(d,p), and the reactivity properties were compared between the natural derivatives of perezone and the three synthesized compounds, and the obtained results exhibited that 9 has the best properties to bind with PARP-1. Finally, it is important to mention that 9 displays significant inhibitory activity against MDA-MB-231 and MCF-7 cells, i.e., 145.01 and 83.17 µM, respectively.

Health-related quality of life and depressive symptoms in Friedreich ataxia.

PURPOSE: Friedreich ataxia (FRDA) is a chronic, progressive and highly disabling cerebellar degenerative disease. Despite this, little attention has been paid to the health-related quality of life (HRQOL) in this disease. The aim of the present study was to assess FRDA patients' perception of HRQOL and to determine the influence of depression, and demographic and clinical variables. METHOD: The sample consisted of 62 patients with genetically confirmed FRDA. The SF-36 Health Survey was used to assess HRQOL. Depressive symptoms were evaluated with the Beck Depression Inventory-II. RESULTS: FRDA patients' mean scores were significantly lower than the values for the Spanish population in all SF36 dimensions. Average z scores ranged from - 5.5 in physical functioning to - 0.48 in mental health. Age and clinical variables were significant predictors of HRQOL in only several dimensions, whereas BDI scores were able to predict a significant percentage of variance in all SF36 dimensions, except physical functioning. CONCLUSIONS: Our study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.

Cognitive characterization of SCAR10 caused by a homozygous c.132dupA mutation in the ANO10 gene.

Autosomal recessive spinocerebellar ataxia type 10 (SCAR10) caused by a homozygous c.132dupA mutation in the anoctamin 10 gene is infrequent and little is known about its cognitive profile. Three siblings (1 male) with this mutation were assessed with a neuropsychological battery measuring multiple cognitive domains. The deficits observed in one patient were in executive functions whereas the other two patients showed deficits in practically all the functions. Cognitive impairment seems to be a characteristic of the SCAR10 produced by this mutation, with a range from mild impairment, especially involving prefrontal systems, to a severe cognitive impairment suggesting widespread cerebral involvement.

Depressive symptoms in Friedreich ataxia.

Background/Objective: Almost no attention has been paid to depression in Friedreich ataxia (FRDA), a highly disabling cerebellar degenerative disease. Our aim was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. Method: The study groups consisted of 57 patients with a diagnosis of FRDA. The Beck Depression Inventory-II was used to assess symptoms of depression. Speed of information processing was measured with a Choice Reaction time task. Results: The mean BDI score for patients was significantly higher than the mean score in the general population. Twenty one percent of participants scored in the moderate/severe range. A Cognitive-Affective score and a Somatic-Motivational score was calculated for each patient. Patients' scores in both dimensions were significantly higher than the scores in the general population. Demographic and disease variables were not related with symptoms of depression, except for severity of ataxia. Depressive symptoms predict cognitive reaction times. The greater proportion of variance was explained by the Cognitive-Affective dimension. Conclusions: Our data show that both somatic-motivational and cognitive affective symptoms of depression are frequent in individuals with FRDA. In addition, depressive symptoms may influence cognition, especially, the cognitive and affective symptoms.

Antecedentes/Objetivo: La depresión en la ataxia de Friedreich (FRDA), una enfermedad degenerativa cerebelosa altamente incapacitante, ha recibido poca atención. Nuestro objetivo es evaluar la presencia y el perfil de los síntomas depresivos en FRDA y su relación con variables clínico-demográficas y la velocidad de procesamiento cognitivo. Método: Se estudiaron 57 pacientes con diagnóstico de FRDA. Se usó el Inventario de Depresión de Beck-II para evaluar los síntomas de depresión. La velocidad de procesamiento se midió con una tarea de tiempos de reacción. Resultados: La puntuación media de los pacientes en el BDI fue significativamente mayor que en la población general. El 21% de los participantes obtuvo puntuaciones en el rango moderado/grave. Se calculó una puntuación cognitiva-afectiva y una puntuación somática-motivacional para cada paciente. Las puntuaciones en ambas dimensiones fueron significativamente mayores que en la población general. Las variables clínico-demográficas no estaban relacionadas con los síntomas de depresión, a excepción de la gravedad de la ataxia. Los síntomas depresivos predicen los tiempos de reacción cognitivos. Conclusiones: Nuestros datos muestran que en la FRDA son frecuentes los síntomas de depresión, tanto los síntomas somático-motivacionales como los cognitivo-afectivos. Además, los síntomas de depresión pueden influir en la cognición, especialmente, los de tipo cognitivo-afectivo.

Depressive symptoms in Friedreich ataxia / Síntomas depresivos en la ataxia de Friedreich

Background/Objective: Almost no attention has been paid to depression in Friedreich ataxia (FRDA), a highly disabling cerebellar degenerative disease. Our aim was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. Method: The study groups consisted of 57 patients with a diagnosis of FRDA. The Beck Depression Inventory-II was used to assess symptoms of depression. Speed of information processing was measured with a Choice Reaction time task. Results: The mean BDI score for patients was significantly higher than the mean score in the general population. Twenty one percent of participants scored in the moderate/ severe range. A Cognitive-Affective score and a Somatic-Motivational score was calculated for each patient. Patients' scores in both dimensions were significantly higher than the scores in the general population. Demographic and disease variables were not related with symptoms of depression, except for severity of ataxia. Depressive symptoms predict cognitive reaction times. The greater proportion of variance was explained by the Cognitive-Affective dimension. Conclusions: Our data show that both somatic-motivational and cognitive affective symptoms of depression are frequent in individuals with FRDA. In addition, depressive symptoms may influence cognition, especially, the cognitive and affective symptoms (AU)

Antecedentes/Objetivo: La depresión en la ataxia de Friedreich (FRDA), una enfermedad degenerativa cerebelosa altamente incapacitante, ha recibido poca atención. Nuestro objetivo es evaluar la presencia y el perfil de los síntomas depresivos en FRDA y su relación con variables clínico-demográficas y la velocidad de procesamiento cognitivo. Método: Se estudiaron 57 pacientes con diagnóstico de FRDA. Se usó el Inventario de Depresión de Beck-II para evaluar los síntomas de depresión. La velocidad de procesamiento se midió con una tarea de tiempos de reacción. Resultados: La puntuación media de los pacientes en el BDI fue significativamente mayor que en la población general. El 21% de los participantes obtuvo puntuaciones en el rango moderado/grave. Se calculó una puntuación cognitiva-afectiva y una puntuación somática-motivacional para cada paciente. Las puntuaciones en ambas dimensiones fueron significativamente mayores que en la población general. Las variables clínico-demográficas no estaban relacionadas con los síntomas de depresión, a excepción de la gravedad de la ataxia. Los síntomas depresivos predicen los tiempos de reacción cognitivos. Conclusiones: Nuestros datos muestran que en la FRDA son frecuentes los síntomas de depresión, tanto los síntomas somáticomotivacionales como los cognitivo-afectivos. Además, los síntomas de depresión pueden influir en la cognición, especialmente, los de tipo cognitivo-afectivo (AU)

Novel phthalocyaninatobis(alkylcarboxylato)silicon(IV) compounds: NMR data and X-ray structures to study the spacing provided by long hydrocarbon tails that enhance their solubility.

The reaction between trans-PcSiCl2 (1) and the potassium salts of six fatty acids (2 a-2 f) led to the trans-PcSi[OOC(CH2)nCH3]2 compounds (3 a-3 f), which were characterised by elemental analysis, IR, UV/Vis and 1H, 13C, and 29Si NMR spectroscopy. From a detailed study of the NMR spectra, the strong anisotropic currents of the Pc macrocycle were found to have an effect on up to the sixth methylenic group. As expected, the length of the hydrocarbon tail does not affect the chemical shift of the 29Si nucleus of any of the compounds, appearing at around -222.6. The structures of PcSi[OOC(CH2)nCH3]2, where n = 7, 10, 12, 13 and 20, were determined by X-ray crystallography. All the compounds were found to be triclinic with a P1 space group. In all cases the observed crystallographic pseudosymmetry is Ci and the asymmetric unit consists of half a molecule. The silicon atom is at the centre of a distorted octahedron and hence its coordination number is six. The carboxylate fragments are in a trans configuration with respect to the Pc macrocycle. The supramolecular structures are discussed in detail herein. The correlation between the 1H NMR chemical shifts and the position of the corresponding carbon atoms in the hydrocarbon tail reveals that the dicarboxylate substituents exhibit a spacer-like behaviour that enhances the solubility. A detailed study of the tail variable allowed us to evaluate the loss of radial shielding along the Pc2- ligand.

Mass spectrometric studies of cyclopentanol derivatives in the reductive coupling of alpha,beta-unsaturated ketones assisted by samarium diiodide.

The mass spectrometric fragmentations of a series of cyclopentanol derivatives in positive fast-atom bombardment (FAB(+)) mode were investigated. The corresponding pathways proposed were confirmed by MS/MS data obtained using linked scans at constant B/E, high-resolution accurate mass data, and comparisons with corresponding information for a specifically deuterated molecule.