Browse by author
Lookup NU author(s): Professor Roger Griffin,
Professor Bernard Golding,
Dr Ian Hardcastle,
Justin John James Leahy,
Dr Laurent Rigoreau,
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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 IC50 values ranged from 0.19 to > 10 muM), 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-1-7,8-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; IC50 = 0.19 muM) 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 doze modification factor of 2.3 at 10% survival being observed with an inhibitor concentration of 5 PM. This study identified these structural classes as novel DNA-PK inhibitors and delineated initial structure activity relationships against DNA-PK.
Author(s): Griffin RJ, Fontana G, Golding BT, Guiard SL, Hardcastle IR, Leahy JJJ, Martin N, Richardson C, Rigoreau LJM, Stockley ML, Smith GCM
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Altmetrics provided by Altmetric