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Issue 1, 2019
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Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase

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Abstract

Altered expression or hyperactivation of anaplastic lymphoma kinase (ALK), as a consequence of translocations or point mutations, is one of the main oncogenic drivers in non-small cell lung cancer. Using structure-based design and in vitro enzyme assays, we identified 3-heteroarylcoumarin as a new template for the development of novel fluorescent ALK inhibitors. Molecular simulation provided structural insights for the design of 3-heteroarylcoumarin derivatives, which were easily prepared through efficient synthetic approaches including direct C–H cross coupling. Importantly, these coumarin-based ALK inhibitors can be tracked using microscopy techniques: we illustrated the use of the most potent compound in this series, 5a, (ALK/IC50 = 0.51 μM, λemi = 500 nm, ϕF = 0.29) to monitor its subcellular distribution pattern by confocal fluorescence microscopy.

Graphical abstract: Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase

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Supplementary files

Article information


Submitted
17 Nov 2018
Accepted
05 Dec 2018
First published
06 Dec 2018

Org. Biomol. Chem., 2019,17, 186-194
Article type
Paper

Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase

S. Mah, J. Jang, D. Song, Y. Shin, M. Latif, Y. Jung and S. Hong, Org. Biomol. Chem., 2019, 17, 186
DOI: 10.1039/C8OB02874E

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