Chemical synthesis and biological activity of novel brominated 7-deazaadenosine-3',5'-cyclic monophosphate derivatives

Bioorg Med Chem. 2019 Apr 15;27(8):1704-1713. doi: 10.1016/j.bmc.2019.03.024. Epub 2019 Mar 12.

Abstract

Synthetic derivatives of cyclic adenosine monophosphate, such as halogenated or other more hydrophobic analogs, are widely used compounds, to investigate diverse signal transduction pathways of eukaryotic cells. This inspired us to develop cyclic nucleotides, which exhibit chemical structures composed of brominated 7-deazaadenines and the phosphorylated ribosugar. The synthesized 8-bromo- and 7-bromo-7-deazaadenosine-3',5'-cyclic monophosphates rank among the most potent activators of cyclic nucleotide-regulated ion channels as well as cAMP-dependent protein kinase. Moreover, these substances bind tightly to exchange proteins directly activated by cAMP.

Keywords: CNG and HCN channels; Epac1 and Epac2; Protein kinase A; cAMP derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Animals
  • Cyclic AMP / analogs & derivatives*
  • Cyclic AMP / chemical synthesis
  • Cyclic AMP / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide-Gated Cation Channels / agonists
  • Cyclic Nucleotide-Gated Cation Channels / metabolism
  • Enzyme Activation / drug effects
  • Guanine Nucleotide Exchange Factors / agonists
  • Guanine Nucleotide Exchange Factors / metabolism
  • Halogenation
  • Humans
  • Mice

Substances

  • Cyclic Nucleotide-Gated Cation Channels
  • Guanine Nucleotide Exchange Factors
  • RAPGEF3 protein, human
  • RAPGEF4 protein, human
  • 7-deazaadenine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Adenine