RESUMEN
2-Chloroacetylamino-pyrrolo[1,2-a]azepine-3-ethyl ester 3 was synthesized, condensed with ammonium thiocyanate to obtain a hybrid molecule of pyrrolo [1,2-a]azepine and thiazolidinone moiety 4. Coupling of the obtained hybrid molecule with the appropriate aldehydes or diazonium salt afforded novel substituted hybrids 5a,b and 6. Chemical structures were confirmed by spectral and elemental analysis. The synthesized compounds were tested on liver Hep3B, lung A549, breast MCF7 cancer cell lines and normal fibroblast cells as well, using sulforhodamine-B assay method. Compound 5a showed to be potent and selective to lung A549 cancer cell line (IC50 = 13 nM/mL, S.I. = 2.9). The most potent one against MCF7 was compound 4 with IC50 value equals 12 nM/mL and S.I. = 1.4. Compounds 5b, 6 exhibited high potency and selectivity towards Hep3B cancer cells with IC50 and S.I. equal 15 nM/mL, 10.8 and 9 nM/mL, 285, respectively. The ability of the synthesized compounds 3-6 to act as modulators for cyclin dependent kinases was explored through molecular docking studies.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Azepinas/síntesis química , Azepinas/farmacología , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Pirroles/síntesis química , Pirroles/farmacología , Antineoplásicos/metabolismo , Azepinas/metabolismo , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/metabolismo , Relación Estructura-ActividadRESUMEN
Hepcidin is a peptide hormone that regulates homeostasis in iron metabolism. It binds to the sole known cellular iron exporter ferroportin (Fpn), triggers its internalization, and thereby modulates the efflux of iron from cells. This functional property has been adopted in this study to assess the bioactivity and potency of a range of novel fluorescent hepcidin analogues. Hepcidin was selectively labeled with 6-carboxyfluorescein (CF) and 6-carboxytetramethylrhodamine (TMR) using Fmoc solid phase peptide chemistry. Internalization of Fpn by hepcidin was assessed by high-content microscopic analysis. Both K18- and M21K-labeled hepcidin with TMR and CF exhibited measurable potency when tested in cultured MDCK and T47D cells expressing human ferroportin. The bioactivity of the labeled hepcidin varies with the type of fluorophore and site of attachment of the fluorophores on the hepcidin molecule.