Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols
Author(s)
Loas, Andrei Ioan; Radford, Robert John; Liang, Alexandria D; Lippard, Stephen J.
DownloadLippard_Solid-phase.pdf (1.749Mb)
PUBLISHER_CC
Publisher with Creative Commons License
Creative Commons Attribution
Terms of use
Metadata
Show full item recordAbstract
We describe a modular, synthetically facile solid-phase approach aimed at separating the fluorescent reporter and binding unit of small-molecule metal-based sensors. The first representatives contain a lysine backbone functionalized with a tetramethylrhodamine fluorophore, and they operate by modulating the oxidation state of a copper ion ligated to an [N4] (cyclam) or an [N2O] (quinoline-phenolate) moiety. We demonstrate the selectivity of their Cu(II) complexes for sensing nitroxyl (HNO) and thiols (RSH), respectively, and investigate the mechanism responsible for the observed reactivity in each case. The two lysine conjugates are cell permeable in the active, Cu(II)-bound forms and retain their analyte selectivity intracellularly, even in the presence of interfering species such as nitric oxide, nitrosothiols, and hydrogen sulfide. Moreover, we apply the new probes to discriminate between distinct levels of intracellular HNO and RSH generated upon stimulation of live HeLa cells with ascorbate and hydrogen sulfide, respectively. The successful implementation of the lysine-based sensors to gain insight into biosynthetic pathways validates the method as a versatile tool for producing libraries of analogues with minimal synthetic effort.
Date issued
2015-05Department
Massachusetts Institute of Technology. Department of ChemistryJournal
Chemical Science
Publisher
Royal Society of Chemistry (RSC)
Citation
Loas, Andrei, Robert J. Radford, Alexandria Deliz Liang, and Stephen J. Lippard. "Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols." Chemical Science 6 (2015), pp. 4131-4140.
Version: Final published version
ISSN
2041-6520
2041-6539