Pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR

Eur J Med Chem. 2018 Oct 5:158:428-441. doi: 10.1016/j.ejmech.2018.09.032. Epub 2018 Sep 12.

Abstract

Aurora A, Aurora B and Kinase Insert Domain-containing Receptor (KDR) play essential roles in sustained cancer growth. In the present study, eighteen pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives were designed and synthesized. Most of the prepared compounds exhibited obviously enzymatic (Aurora A/B and KDR) activities. Among these analogs, compound 17g displayed significant Aurora A/B and KDR potencies with IC50 values of 46.2 nM, 37.6 nM and 21.6 nM, respectively. The results of further biological assays showed that compound 17g possessed moderate anti-proliferative activities against SNU-5, MKN-45 and MKN-74 cells lines, induced G2/M cell cycle arrest and apoptosis in MKN-45, MKN-74, SGC-7901 and SNU-5 cell lines, provided acceptable pharmacokinetic profiles (F = 63.8%), and inhibited the proliferation of SNU-5 tumors in vivo of mice. All of the above results suggested that pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine could be developed as a promising scaffold of multiple Aurora A/B and KDR inhibitors and 17g was worth of further research as a multi-targeted lead compound.

Keywords: Anticancer; Aurora A; Aurora B; Heterocyclic; KDR; Multi-targeted.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / metabolism
  • Aurora Kinase B / antagonists & inhibitors*
  • Aurora Kinase B / metabolism
  • Azepines / chemistry*
  • Azepines / pharmacokinetics
  • Azepines / pharmacology*
  • Azepines / therapeutic use
  • Cell Line, Tumor
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antineoplastic Agents
  • Azepines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • Aurora Kinase A
  • Aurora Kinase B