Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines

Bioorg Med Chem. 2011 Jul 1;19(13):3983-94. doi: 10.1016/j.bmc.2011.05.032. Epub 2011 May 24.

Abstract

A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Collagen / pharmacology
  • Computer Simulation
  • DNA-Activated Protein Kinase / antagonists & inhibitors*
  • DNA-Activated Protein Kinase / metabolism
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Morpholines / chemical synthesis*
  • Morpholines / chemistry*
  • Morpholines / pharmacology
  • Oxazines / chemical synthesis
  • Oxazines / chemistry*
  • Oxazines / pharmacology
  • Phosphatidylinositol 3-Kinases / chemistry
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemical synthesis*
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Structure-Activity Relationship

Substances

  • 2-morpholin-7-(pyridin-2-ylmethoxy)-4H-naphth(2,1-e)-1,3-oxazin-4-one
  • Morpholines
  • Oxazines
  • Platelet Aggregation Inhibitors
  • Protein Kinase Inhibitors
  • morpholine
  • Collagen
  • Phosphatidylinositol 3-Kinases
  • DNA-Activated Protein Kinase