Design, synthesis and preliminary biological evaluation of C-8 substituted guanine derivatives as small molecular inhibitors of FGFRs

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1556-60. doi: 10.1016/j.bmcl.2015.02.010. Epub 2015 Feb 16.


Two series of C-8 substituted guanine derivatives were synthesized, one bearing 2-amino substitutions and the other bearing 2-acetamide substitutions. Biological activity tests showed that almost all of them possessed some extent of antitumor activities, and were with lower toxicity against normal human liver HL7702 cells than AZD4547 (the positive control). Among them, N-[8-(4-bromo-1H-indol-3-yl)-6-hydroxy-9H-purin-2-yl]-acetamide exhibited a relatively satisfied inhibition against FGFR1 kinase with IC50 of 1.56 μM and specifically against A549 cells with IC50 of 8.28 μM and B16-F10 cells with IC50 of 6.59 μM. Above all, the introduction of large substituents such as indolyl groups at 8-position of the guanine scaffold probably achieves higher selectivity for FGFR1 as compared with AZD4547.

Keywords: Antitumor activity; FGFR; Guanine; Kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Guanine / analogs & derivatives
  • Guanine / chemistry
  • Guanine / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Guanine
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1