title: Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro.
abstract: A diverse range of chromen-2-one, chromen-4-one and pyrimidoisoquinolin-4-one derivatives was synthesized and evaluated for inhibitory activity against the DNA repair enzyme DNA-dependent protein kinase (DNA-PK), with a view to elucidating structure-activity relationships for potency and kinase selectivity. DNA-PK inhibitory activity varied widely over the series of compounds evaluated (IC(50) values ranged from 0.19 to >10 microM), with excellent activity being observed for the 7,8-benzochromen-4-one and pyrimido[2,1-a]isoquinolin-4-one templates. By contrast, inhibitors based on the benzochromen-2-one (coumarin) or 2-aryl-7,8-benzochromen-4-one (flavone) scaffolds were less potent. Crucially, these studies revealed a very constrained structure-activity relationship at the 2-position of the benzopyranone and pyrimido[2,1-a]isoquinolin-4-one pharmacophore, with only a 2-morpholino or 2-(2'-methylmorpholino) group being tolerated at this position. More detailed biological studies conducted with the most potent inhibitor NU7163 (48; IC(50) = 0.19 microM) demonstrated ATP-competitive DNA-PK inhibition, with a K(i) value of 24 nM, and 48 exhibited selectivity for DNA-PK compared with the related enzymes ATM, ATR, mTOR, and PI 3-K (p110alpha). Compound 48 sensitized the HeLa human tumor cell line to the cytotoxic effects of ionizing radiation in vitro, a dose modification factor of 2.3 at 10% survival being observed with an inhibitor concentration of 5 microM. This study identified these structural classes as novel DNA-PK inhibitors and delineated initial structure-activity relationships against DNA-PK.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, The University, Newcastle upon Tyne NE1 7RU, UK.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fontana
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Sophie
authors.initials: S
authors.lastname: Guiard
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Justin J J
authors.initials: JJ
authors.lastname: Leahy
authors.forename: Niall
authors.initials: N
authors.lastname: Martin
authors.forename: Caroline
authors.initials: C
authors.lastname: Richardson
authors.forename: Laurent
authors.initials: L
authors.lastname: Rigoreau
authors.forename: Martin
authors.initials: M
authors.lastname: Stockley
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
mesh_terms: D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C496957:2-(2-methylmorpholin-4-yl)benzo(h)chromen-4-one; D001578:Benzopyrans; D002867:Chromones; D004268:DNA-Binding Proteins; D007546:Isoquinolines; D009025:Morpholines; D009687:Nuclear Proteins; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases