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Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

Lookup NU author(s): Olivier Barbeau, Dr Celine Cano, Professor Roger Griffin, Dr Ian Hardcastle, Emeritus Professor Bill Clegg, Dr Ross Harrington, Professor Bernard Golding

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Abstract

8- Substituted 2- morpholin- 4- yl- quinolin- 4- ones and 9- substituted 2- morpholin- 4- ylpyrido[ 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] dioxane4,6- 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- ylpyrido[ 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- 4yl- 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. Grif. n, J. Med. Chem., 2005, 48, 7829 - 7846).


Publication metadata

Author(s): Barbeau OR, Cano-Soumillac C, Griffin RJ, Hardcastle IR, Smith GCM, Richardson C, Clegg W, Harrington RW, Golding BT

Publication type: Article

Publication status: Published

Journal: Organic & Biomolecular Chemistry

Year: 2007

Volume: 5

Issue: 16

Pages: 2670-2677

ISSN (print): 1477-0520

ISSN (electronic): 1477-0539

URL: http://dx.doi.org/10.1039/b705095j

DOI: 10.1039/b705095j

PubMed id: 18019542


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