title: Toward the development of prochelators as fluorescent probes of copper-mediated oxidative stress.
abstract: A fluorescent sensor prochelator, FlamB (fluorescein hydrizido 2-imidophenylboronic ester), has been developed that selectively probes for copper under conditions of oxidative stress. High levels of hydrogen peroxide trigger the release of a boronic ester masking group from the prochelator to unveil a metal chelator, FlamS (fluorescein hydrizido 2-imidophenol), that provides a modest fluorescence increase in response to Cu(2+) but not other metal ions. X-Ray crystal structures of FlamB, FlamS, and Cu-bound FlamS are all reported. The fluorescence turn-on results from opening of a fluorescein spirolactam ring upon Cu(2+) binding to FlamS in aqueous solution. Oxidation of the aryl boronic ester of FlamB to the metal-binding phenol of FlamS proceeds in organic solvents. However, in aqueous solution a competing mechanism occurs due to hydrolytic instability of the masked prochelator. Hydrolysis of FlamB leads to formation of fluorescein hydrazide, which interacts with copper or H(2)O(2) to produce fluorescein and a significant fluorescence increase.
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708-0346, USA.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Hyman
authors.forename: Clifton J
authors.initials: CJ
authors.lastname: Stephenson
authors.forename: Marina G
authors.initials: MG
authors.lastname: Dickens
authors.forename: Ken D
authors.initials: KD
authors.lastname: Shimizu
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Franz
mesh_terms: D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005452:Fluoresceins / Q000138:chemical synthesis / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000737:chemistry*; D008968:Molecular Conformation; D018384:Oxidative Stress / Q000187:drug effects*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D002614:Chelating Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; C547611:fluorescein hydrizido 2-imidophenol; C547612:fluorescein hydrizido 2-imidophenylboronic ester; D003300:Copper