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Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach

Lookup NU author(s): Dr Ian HardcastleORCiD, Professor Nicola CurtinORCiD, Justin John James Leahy, Martin Stockley, Emeritus Professor Bernard Golding, Dr Laurent Rigoreau, Professor Roger Griffin


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Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]-chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxy-substituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNA-PK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6′, 7′,8′,9′-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 μM. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated. © 2005 American Chemical Society.

Publication metadata

Author(s): Hardcastle I, Cockcroft X, Curtin NJ, El-Murr M, Leahy JJJ, Stockley M, Golding BT, Rigoreau L, Richardson C, Smith G, Griffin RJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2005

Volume: 48

Issue: 24

Pages: 7829-7846

Print publication date: 01/12/2005

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804


DOI: 10.1021/jm050444b

PubMed id: 16302822


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