Blood-brain barrier-permeable fluorone-labeled dieckols acting as neuronal ER stress signaling inhibitors

Abstract We studied the blood–brain barrier (BBB) permeability and intracellular localization of a fluorescein isothiocyanate (FITC)-labeled dieckol ( 1 ) and a rhodamine B-labeled dieckol ( 7 ), for exploring the possible therapeutic application of fluorone-labeled dieckols in neurodegenerative diseases. Both compounds ( 1 & 7 ) were synthesized through a click reaction and were found to be localized in the endoplasmic reticulum (ER) of the two types of brain cell lines (SH-SY5Y and BV-2 cells) tested; they also reduced ER stress in the SH-SY5Y human neuroblastoma cells. In addition, 1 and 7 were shown to pass the BBB in rats upon intravenous administration. Altogether, our study demonstrates, for the first time, that targeted ER-stress reduction in brain cells can be achieved by introducing fluorone–dieckol conjugates into systemic circulation. Therefore, 1 and 7 provide a novel and promising ER-targeting therapeutic strategy for neurodegenerative diseases.