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

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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 M, (emi) = 500 nm, phi(F) = 0.29) to monitor its subcellular distribution pattern by confocal fluorescence microscopy.
Publisher
ROYAL SOC CHEMISTRY
Issue Date
2019-01
Language
English
Article Type
Article
Citation

ORGANIC BIOMOLECULAR CHEMISTRY, v.17, no.1, pp.186 - 194

ISSN
1477-0520
DOI
10.1039/c8ob02874e
URI
http://hdl.handle.net/10203/250118
Appears in Collection
CH-Journal Papers(저널논문)
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