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

J Med Chem. 2005 Jan 27;48(2):569-85. 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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • 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
  • Morpholines / chemical synthesis*
  • Morpholines / chemistry
  • Morpholines / pharmacology
  • Nuclear Proteins
  • 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
  • Stereoisomerism
  • Structure-Activity Relationship


  • 2-(2-methylmorpholin-4-yl)benzo(h)chromen-4-one
  • Benzopyrans
  • Chromones
  • DNA-Binding Proteins
  • Isoquinolines
  • Morpholines
  • Nuclear Proteins
  • Pyrimidines
  • Radiation-Sensitizing Agents
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein Serine-Threonine Kinases