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Issue 16, 2007
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Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

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Abstract

8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones with selected aryl and heteroaryl groups as the substituent have been synthesised as potential inhibitors of DNA-dependent protein kinase. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was utilised in the preparation of 8-substituted 2-morpholin-4-yl-quinolin-4-ones. For this purpose 8-bromo-2-morpholin-4-yl-quinolin-4-one was required as an intermediate. This compound was obtained by adapting a literature route in which thermal cyclocondensation of (2-bromoanilino)-morpholin-4-yl-5-methylene-2,2-dimethyl[1,3]dioxane-4,6-dione afforded 8-bromo-2-morpholin-4-yl-quinolin-4-one. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was also utilised to prepare 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones using 9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one O-trifluoromethanesulfonate as an intermediate. 8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones were both inhibitors of DNA-dependent protein kinase. When the substituent was dibenzothiophen-4-yl, dibenzofuran-4-yl or biphen-3-yl, IC50 values in the low nanomolar range were observed. Interestingly, the pyridopyrimidinones and quinolinones were essentially equipotent with the corresponding 8-substituted 2-morpholin-4-yl-chromen-4-ones previously reported (I. R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El-Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Griffin, J. Med. Chem., 2005, 48, 7829–7846).

Graphical abstract: Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

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Publication details

The article was received on 03 Apr 2007, accepted on 18 Jun 2007 and first published on 05 Jul 2007


Article type: Paper
DOI: 10.1039/B705095J
Citation: Org. Biomol. Chem., 2007,5, 2670-2677
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    Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

    O. R. Barbeau, C. Cano-Soumillac, R. J. Griffin, I. R. Hardcastle, G. C. M. Smith, C. Richardson, W. Clegg, R. W. Harrington and B. T. Golding, Org. Biomol. Chem., 2007, 5, 2670
    DOI: 10.1039/B705095J

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