RESUMEN
The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC50 values of 1.44, 0.46, 1.02, 0.79, and 3.65 µM, respectively, with the most potent inhibitor 3e 13-[(1-(3-nitrophenyl)triazol-4yl)methoxy]-totara-8,11,13-triene). These compounds were evaluated on their antiproliferative effects in a panel of prostate cancer cell lines. Compound 3r inhibited the proliferation of LNCaP, PC3 and DU145 cells at 20 µM, strongly, but also has strong cytotoxic effects on all tested cells.
Asunto(s)
Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Fosfotransferasas (Aceptor de Grupo Alcohol) , Triazoles , Humanos , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Estructura Molecular , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Relación Dosis-Respuesta a Droga , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Simulación del Acoplamiento MolecularRESUMEN
OBJECTIVES: The aim of this study was to examine the longitudinal relationship between job satisfaction and total productivity-related costs, and between job satisfaction and absenteeism and presenteeism costs separately. A secondary aim was to explore whether these relationships differed across job types. METHODS: Linear generalized estimating equation analyses were used to explore the longitudinal relationships. To explore whether the relationships differed across job types, stratified analyses were performed. RESULTS: A significant relationship was found between job satisfaction and total productivity-related costs [ßâ=â&OV0556;-273; 95% confidence interval (95% CI): -407 to -200] and between job satisfaction and presenteeism costs (ßâ=â&OV0556;-276; 95% CI: -367 to -235), but not between job satisfaction and absenteeism costs. These relationships differed across job types. CONCLUSIONS: Higher levels of job satisfaction were longitudinally related to lower total productivity-related costs and presenteeism costs, but not to lower absenteeism costs. These relationships seem to differ across job types.