RESUMO
Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6â¯>â¯500) and potency (HDAC6 IC50â¯<â¯5â¯nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to ΦFâ¯=â¯0.83 in DMSO and 0.38 in aqueous buffer) makes them ideally suited for cellular imaging and visualisation of their cytoplasmic localisation was readily accomplished. Whole organism imaging in zebrafish confirmed both the vascular localisation of the new inhibitors and the impact of HDAC6 inhibition on in vivo development.
Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Hidroxilaminas/química , Quinolinas/química , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Citoplasma/metabolismo , Diagnóstico por Imagem/métodos , Fluorescência , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Hidroxilaminas/síntese química , Hidroxilaminas/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Peixe-Zebra/metabolismoRESUMO
Fluorescence microscopy studies using 4-morpholinoscriptaid (4MS) demonstrated rapid cellular uptake of this scriptaid analogue into the cytoplasm but no nuclear penetration. As 4MS and scriptaid have the same in vitro activity against HDACs and KASUMI-1 cells; 4MS exemplifies a rational approach to subtly modify 'profluorogenic' substrates for intracellular studies.
