title: 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.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea.
authors.forename: Jong Hwan
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea.
authors.forename: Byungkwon
authors.initials: B
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Uhm
authors.affiliation: CEWIT Center for Systems Biology, The State University of New York, Incheon 406-840, South Korea.
authors.forename: Hyeon-Cheol
authors.initials: HC
authors.lastname: Shin
authors.affiliation: Department of Chemical and Biological Engineering, Hanbat National University, Daejeon 305-717, South Korea.
authors.forename: Bong Ho
authors.initials: BH
authors.lastname: Lee
authors.affiliation: College of Medicine, Konyang University, Daejeon 302-718, South Korea.
authors.forename: Yung Choon
authors.initials: YC
authors.lastname: Yoo
authors.affiliation: College of Medicine, Konyang University, Daejeon 302-718, South Korea. Electronic address: kyunglee@konyang.ac.kr.
authors.forename: Kyung Bok
authors.initials: KB
authors.lastname: Lee
authors.affiliation: College of Medicine, Konyang University, Daejeon 302-718, South Korea. Electronic address: jjzzy@konyang.ac.kr.
authors.forename: Seung-Yun
authors.initials: SY
authors.lastname: Han
authors.affiliation: Department of Chemistry, Korea University, Seoul 136-701, South Korea. Electronic address: jongskim@korea.ac.kr.
authors.forename: Jong Seung
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013194:Staining and Labeling / Q000379:methods; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D001572:Benzofurans; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; C503840:dieckol
keywords: Blood-brain barrier; Click reaction; ER localization; Endoplasmic reticulum (ER) stress; Fluorone-labeled dieckols