title: Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase.
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).
authors.affiliation: Northern Institute for Cancer Research, Bedson Building, Newcastle University, Newcastle upon Tyne, UK NE1 7RU.
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Barbeau
authors.forename: Celine
authors.initials: C
authors.lastname: Cano-Soumillac
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Caroline
authors.initials: C
authors.lastname: Richardson
authors.forename: William
authors.initials: W
authors.lastname: Clegg
authors.forename: Ross W
authors.initials: RW
authors.lastname: Harrington
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
mesh_terms: D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011744:Pyrimidinones; D015363:Quinolones; D051747:DNA-Activated Protein Kinase