Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives

Org Biomol Chem. 2012 Sep 7;10(33):6747-57. doi: 10.1039/c2ob26035b. Epub 2012 Jul 19.

Abstract

Substitution at the 7-position of the chromen-4-one pharmacophore of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Chromones / chemical synthesis
  • Chromones / chemistry*
  • Chromones / pharmacology*
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • DNA-Activated Protein Kinase / chemistry
  • DNA-Activated Protein Kinase / metabolism
  • Humans
  • Models, Molecular
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine

Substances

  • 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
  • Chromones
  • Morpholines
  • Protein Kinase Inhibitors
  • DNA-Activated Protein Kinase