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Tubulin is a heterodimeric protein composed of α- and β-subunits, which polymerize to form the cell’s microtubules. The latter are key components in mitotic spindle formation and essential targets in anticancer therapy. Compounds such as paclitaxel, tubulysins, dolastatins and synthetic analogues of these latter compounds, including cemadotin, exert their cytotoxic effects by disrupting microtubule dynamics. Previously, we reported the production and anticancer activity of a library of cemadotin analogues featuring a C-terminal tertiary amide functionalized with a variety of N-substituents, thus resulting in compounds occurring as a mixture of amide rotamers. Here we describe a comprehensive NMR and conformational study that provides new insights into the effect of the conformational equilibrium on the binding mode of the novel cemadotin analogues to the tubulin target. The conformational behavior of the isomer equilibrium of cemadotin’s terminal amide bond was investigated by TOCSY and ROESY NMR experiments, which allowed the identification and quantification of individual rotamer populations. A slow interconversion between the s-cis and s-trans amide rotamers was observed under standard NMR conditions (25 °C), indicating a significant energy barrier and conformational rigidity. Molecular docking and saturation transfer difference (STD) NMR experiments were performed with a representative analogue and tubulin to assess the binding mode. The results revealed that the s-trans rotamer is the predominant conformer in solution and exhibits a more favorable interaction with tubulin compared to the s-cis isomer, thus helping to understand the conformational requirements for an improved tubulin binding and the inhibition of the polymerization process.

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.

Chagas disease is a serious health problem in Central and South America for which effective treatment is not currently available. This illness is caused by the protozoa Trypanosoma cruzi , a species that relies on a thiol-based metabolism to regulate oxidative stress. Trypanothione reductase enzyme plays a central role in the metabolic pathway of the parasite. In this work, a virtual screening of a library of novel thiadiazine derivatives against trypanothione reductase using molecular docking was performed. Four different series of hybrid ligands having in the structure one or two peptoid moieties (series I and II) or the tetrazole ring (series III and IV) were considered. An ad hoc numerical index called poses ratio was introduced to interpret the results of the docking analysis and to establish relevant structure-interaction relationships. In addition, six binding modes were found for the ligands with the highest populated conformational clusters after applying contact-based analysis. The most regular and relevant were binding modes I and II, found mainly for ligands from series I. A subsequent molecular docking on human glutathione reductase enzyme allowed to assess the possible cytotoxicity of the ligands towards human cells. A selective binding profile was found for ligands with interactions in the Hydrophobic cleft, the spermidine and the Z subsites inside the active site of trypanothione reductase. At the end of the study, new thiadiazine-based compounds were identified as plausible candidates to selectively inhibit the parasitic enzyme. Graphic abstract

The increase of requests for implant-supported prosthesis (ISP) with zirconia as infrastructure has attracted a lot of attention due to its esthetics, biocompatibility, and survival rate similar to metallic infrastructure. The aim of this study was to evaluate the influence of two different framework materials on stress distribution over a bone tissue-simulating material. Two ISP were modeled and divided into two infrastructure materials: titanium (Ti) and zirconia. Then, these bars were attached to a modeled jaw with polyurethane properties to simulate bone tissue. An axial load of 200 N was applied on a standardized area for both systems. Maximum principal stress (MPS) on solids and microstrain (MS) generated through the jaw were analyzed by finite element analysis. According to MS, both models showed strains on peri-implant region of the penultimate (same side of the load application) and central implants. For MPS, more stress concentration was slightly higher in the left posterior region for Ti's bar. In prosthetic fixation screws, the MPS prevailed strongly in Ti protocol, while for zirconia's bar, the cervical of the penultimate implant was the one that highlighted larger areas of possible damages. The stress generated in all constituents of the system was not significantly influenced by the framework's material. This allows suggesting that in cases without components, the use of a framework in zirconia has biomechanical behavior similar to that of a Ti bar.

ABSTRACT Objective: compare the quality of life (QOL) of aged residents in homes for aged people with or without symptoms of depression, and identify social, physical activity; leisure; health and basic activities of daily living (ADL) variables that correlate with QOL scores. Method: cross-sectional study conducted with 101 institutionalized aged. Multiple linear regression was used for data analysis. Results: symptoms of depression changed negatively the QOL in the domains: autonomy; present, past and future activities; social participation; intimacy and total score. Dependent aged presented lower QOL for the performance of ADL in the domains: autonomy; social participation and total score; dancing without limitation of movement; liking the residential and not presenting symptoms of depression were the variables that positively influenced the QOL of the aged. Conclusion: social and psychological support, good living conditions and stimulating assistance can improve the QOL of institutionalized elderlies. RESUMEN Objetivo: comparar la calidad de vida (CV) de los ancianos residentes en instituciones de larga permanencia con o sin síntomas de depresión, e identificar variables sociales, de actividad física, de ocio, de salud y de actividades básicas de la vida diaria (ABVD) que se correlacionan con las puntuaciones de CV. Método: estudio transversal realizado con 101 ancianos institucionalizados. Para el análisis de los datos se utilizó la regresión lineal múltiple. Resultados: los síntomas de depresión cambiaron negativamente la CV en los dominios: autonomía; actividades presentes, pasadas y futuras; participación social; intimidad y puntuación total. Los ancianos dependientes para la realización de la ABVD tuvieron menor CV en los dominios: autonomía, participación social y puntuación total; bailar sin limitación de movimiento, gustar de lo hogar, y no mostrar síntomas de depresión, fueron las variables que influenciaron de forma positiva en la CV de los ancianos. Conclusión: el apoyo social y psicológico, unas buenas condiciones de vida y una asistencia estimulante pueden mejorar la calidad de vida de los ancianos institucionalizados. RESUMO Objetivo: comparar a qualidade de vida (QV) de idosos residentes em instituições de longa permanência com ou sem sinais de depressão, e identificar variáveis sociais, de atividade física, lazer, saúde e atividades básicas da vida diária (ABVD) que se correlacionam aos escores de QV. Método: estudo transversal realizado com 101 idosos institucionalizados. A regressão linear múltipla foi usada para a análise dos dados. Resultados: sinais de depressão alteraram negativamente a QV nos domínios: autonomia, atividades presentes, passadas e futuras, participação social, intimidade e escore total; idosos dependentes para a realização das ABVD apresentaram QV inferior nos domínios: autonomia, participação social e escore total; dançar sem limitação de movimento, gostar do residencial e não apresentar sinais de depressão foram as variáveis que influenciaram positivamente a QV dos idosos. Conclusão: suporte social e psicológico, boas condições de moradia e assistência estimuladora podem melhorar a QV de idosos institucionalizados.