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

• Published in: Journal of medicinal chemistry Vol. 48; no. 2; pp. 569 - 585
• Main Authors: Griffin, Roger J, Fontana, Gabriele, Golding, Bernard T, Guiard, Sophie, Hardcastle, Ian R, Leahy, Justin J. J, Martin, Niall, Richardson, Caroline, Rigoreau, Laurent, Stockley, Martin, Smith, Graeme C. M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.01.2005; Amer Chemical Soc
• Subjects: Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; Chemistry, Medicinal; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; DNA-Activated Protein Kinase; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacology; Nuclear Proteins; Pharmacology & Pharmacy; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Radiation, Ionizing; Radiation-Sensitizing Agents - chemical synthesis; Radiation-Sensitizing Agents - chemistry; Radiation-Sensitizing Agents - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; CATALYTIC SUBUNIT; REPAIR; LY294002; PHOSPHORYLATION; PHOSPHATIDYLINOSITOL 3-KINASE; ATM; BINDING; WORTMANNIN; REQUIREMENT
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049526a

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 μM), 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; IC50 = 0.19 μM) 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 μM. This study identified these structural classes as novel DNA-PK inhibitors and delineated initial structure−activity relationships against DNA-PK.