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Issue 10, 2017
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Thiophene bridged aldehydes (TBAs) image ALDH activity in cells via modulation of intramolecular charge transfer

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Abstract

Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of an aldehyde to a carboxylic acid and are implicated in the etiology of numerous diseases. However, despite their importance, imaging ALDH activity in cells is challenging due to a lack of fluorescent imaging probes. In this report, we present a new family of fluorescent probes composed of an oligothiophene flanked by an aldehyde and an electron donor, termed thiophene-bridged aldehydes (TBAs), which can image ALDH activity in cells. The TBAs image ALDH activity via a fluorescence sensing mechanism based on the modulation of intramolecular charge transfer (ICT) and this enables the TBAs and their ALDH-mediated oxidized products, thiophene-bridged carboxylates (TBCs), to have distinguishable fluorescence spectra. Herein, we show that the TBAs can image ALDH activity in cells via fluorescence microscopy, flow cytometry, and in a plate reader. Using TBA we were able to develop a cell-based high throughput assay for ALDH inhibitors, for the first time, and screened a large, 1460-entry electrophile library against A549 cells. We identified α,β-substituted acrylamides as potent electrophile fragments that can inhibit ALDH activity in cells. These inhibitors sensitized drug-resistant glioblastoma cells to the FDA approved anti-cancer drug, temozolomide. The TBAs have the potential to make the analysis of ALDH activity in cells routinely possible given their ability to spectrally distinguish between an aldehyde and a carboxylic acid.

Graphical abstract: Thiophene bridged aldehydes (TBAs) image ALDH activity in cells via modulation of intramolecular charge transfer

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Publication details

The article was received on 10 Jul 2017, accepted on 01 Aug 2017 and first published on 24 Aug 2017


Article type: Edge Article
DOI: 10.1039/C7SC03017G
Citation: Chem. Sci., 2017,8, 7143-7151
  • Open access: Creative Commons BY-NC license
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    Thiophene bridged aldehydes (TBAs) image ALDH activity in cells via modulation of intramolecular charge transfer

    S. Maity, C. M. Sadlowski, J. George Lin, C. Chen, L. Peng, E. Lee, G. K. Vegesna, C. Lee, S. Kim, D. Mochly-Rosen, S. Kumar and N. Murthy, Chem. Sci., 2017, 8, 7143
    DOI: 10.1039/C7SC03017G

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