The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents

Bioorg Med Chem. 2015 May 15;23(10):2408-23. doi: 10.1016/j.bmc.2015.03.061. Epub 2015 Mar 30.

Abstract

A series of eleven conformationally restricted, 4-substituted 2,6-dimethylfuro[2,3-d]pyrimidines was designed to explore the bioactive conformation required for dual inhibition of microtubule assembly and receptor tyrosine kinases (RTKs), and their biological activities are reported. All three rotatable single bonds in the lead compound 1 were sequentially restricted to address the role of each in SAR for microtubule and RTK inhibitory effects. Compounds 2, 3, 7 and 10 showed microtubule depolymerizing activity comparable to or better than the lead 1, some with nanomolar EC50 values. While compound 8 had no effect on microtubules, 8 and 10 both showed potent RTK inhibition with nanomolar IC50s. These compounds confirm that the bioactive conformation for RTK inhibition is different from that for tubulin inhibition. The tetrahydroquinoline analog 10 showed the most potent dual tubulin and RTK inhibitory activities (low nanomolar inhibition of EGFR, VEGFR2 and PDGFR-β). Compound 10 has highly potent activity against many NCI cancer cell lines, including several chemo-resistant cell lines, and could serve as a lead for further preclinical studies.

Keywords: Antitubulin; Conformation restriction; Multitargeted inhibitors; Receptor tyrosine kinase inhibitors; Synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis*
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chick Embryo
  • Drug Design
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism
  • Furans / chemical synthesis*
  • Furans / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Microtubules / chemistry
  • Microtubules / drug effects*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Neovascularization, Physiologic / drug effects
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta / chemistry
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Structure-Activity Relationship
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Furans
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Tubulin Modulators
  • EGFR protein, human
  • ErbB Receptors
  • KDR protein, human
  • Receptor, Platelet-Derived Growth Factor beta
  • Vascular Endothelial Growth Factor Receptor-2