RESUMEN
Synthesis of paclitaxel-penetratin (pAntp) constructs, in which the 2'- or 7-position of paclitaxel was used as the attachment site for linker connecting the drug and peptide moieties, is described. Paclitaxel-2'-pAntp[43-58]-NH(2)3b and paclitaxel-2'-pAntp[52-58]-NH(2)3c showed excellent antitumour activity against human lung and breast cancer cell lines. These conjugates were highly soluble and stable with a half-life of >8h under cell culture conditions. The drug-peptide conjugates may be therapeutically useful due to improved pharmaceutical properties.
Asunto(s)
Antineoplásicos Fitogénicos/química , Proteínas Portadoras/química , Paclitaxel/química , Secuencia de Aminoácidos , Antineoplásicos Fitogénicos/farmacocinética , Barrera Hematoencefálica , Línea Celular Tumoral , Péptidos de Penetración Celular , Resistencia a Múltiples Medicamentos , Semivida , Humanos , Datos de Secuencia Molecular , Paclitaxel/farmacocinética , Relación Estructura-ActividadRESUMEN
AIM: To study the time course and progression of pressure overload-induced left ventricular hypertrophy METHODS: Left ventricular hypertrophy was induced in rats by abdominal aorta constriction and assessed at different time points (10, 15, 20, 25, 35, and 45 days) after operation. RESULTS: The cardiac index (the ratio of heart weight to body weight) in aortic-banded animals was characterised by phasic changes when compared with the sham operated and the control animals. In aortic-banded rats the cardiac index rose sharply at days 10 and 15 after operation. This sharp increase was followed by a phase of slight increase (day 20), and then it again sharply increased (day 25). At the remaining time points (days 35 and 45) the cardiac index was significantly increased in comparison with that of the sham operated and the control animals but the increase diminished gradually. CONCLUSION: Our results suggest that left ventricular hypertrophy develops not in a linear but in a phasic way. Yet, the experimental model we used produced a relatively stable left ventricular hypertrophy.
Asunto(s)
Hipertrofia Ventricular Izquierda/fisiopatología , Análisis de Varianza , Animales , Aorta Abdominal/fisiopatología , Progresión de la Enfermedad , Ligadura , Masculino , Ratas , Ratas Wistar , Presión Ventricular/fisiologíaRESUMEN
Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure-activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure-activity relationship.
