Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Hardcastle, I.R. et al.

Hardcastle, Cockcroft, Curtin, El-Murr, Leahy, Stockley, Golding, Rigoreau, Richardson, Smith, Griffin,

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

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 microM. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.[1]

References

Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach. Hardcastle, I.R., Cockcroft, X., Curtin, N.J., El-Murr, M.D., Leahy, J.J., Stockley, M., Golding, B.T., Rigoreau, L., Richardson, C., Smith, G.C., Griffin, R.J. J. Med. Chem. (2005) [Pubmed]

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