Synthesis of novel 7-substituted pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6784-8. doi: 10.1016/j.bmcl.2013.10.019. Epub 2013 Oct 17.

Abstract

The efficient synthesis of 7-substituted pyrido[2',3':4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki-Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49 nM and proved to be specific to CLK1 among the panel of tested kinases.

Keywords: Dimroth rearrangement; Formamide degradation; Microwave-assisted chemistry; Serine/threonine kinases inhibitors; Suzuki–Miyaura cross-coupling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry*
  • Amines / metabolism
  • Amines / pharmacology*
  • Catalysis
  • Cyclization
  • Enzyme Activation / drug effects
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Microwaves
  • Palladium / chemistry
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyridines / chemistry
  • Pyrimidines / chemistry
  • Structure-Activity Relationship

Substances

  • 3,5-dibromopyridine
  • 7-(2,4-dichlorophenyl)pyrido(2',3'-4,5)furo(3,2-d)pyrimidin-4-amine
  • Amines
  • Heterocyclic Compounds, 3-Ring
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Palladium
  • Protein Serine-Threonine Kinases
  • pyrimidine