Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols
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Lippard_Solid-phase.pdf
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1.75 MB
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Author(s)
Loas, Andrei Ioan
Radford, Robert John
Liang, Alexandria D
Lippard, Stephen J.
Date Issued
May 2015
Journal
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
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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Creative Commons Attribution-NonCommercial 3.0 Unported licence
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DOI of Published Version
https://doi.org/10.1039/c5sc00880h
