Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism.

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Published in Communications Chemistry, v. 4, article no. 162.

© The Author(s) 2021

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L.S. and A.M. acknowledge the Spanish Multi-MetDrugs network (RED2018-102471-T) for fruitful discussion and the Severo Ochoa Centres of Excellence Program of the Spanish State Research Agency—Grant No. CEX2018-000867-S (DIPC). This work was partially supported by Austria–Ukraine collaboration projects granted to W.B. and R.S. in 2011–2014 (WTZ UA 02/2011 and UA 01/2013), and to P.H. and R.P in 2019–2020 (WTZ UA 03/2019).

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The authors declare that the data supporting the findings of this study are available within the article and Supplementary Information file or from the corresponding author upon reasonable request. Furthermore, the XYZ coordinates for the DFT-optimized LE–NACox(C), LE–NACox(C,D), and LE–NACred are available in Supplementary Data 1, 2 and 3, respectively.

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Supplementary information

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Description of additional supplementary files

42004_2021_600_MOESM3_ESM.txt (3 kB)
Supplementary data 1

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Supplementary data 2

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Supplementary data 3

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Reporting summary