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Issue 7, 2015
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Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols

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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.

Graphical abstract: Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols

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Publication details

The article was received on 10 Mar 2015, accepted on 05 May 2015 and first published on 19 May 2015


Article type: Edge Article
DOI: 10.1039/C5SC00880H
Citation: Chem. Sci., 2015,6, 4131-4140
  • Open access: Creative Commons BY-NC license
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    Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols

    A. Loas, R. J. Radford, A. Deliz Liang and S. J. Lippard, Chem. Sci., 2015, 6, 4131
    DOI: 10.1039/C5SC00880H

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