The synthesis and anti-tumour properties of novel 4-substituted phthalazinones as Aurora B kinase inhibitors

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127556. doi: 10.1016/j.bmcl.2020.127556. Epub 2020 Sep 14.

Abstract

A series of novel 4-substituted phthalazinones as Aurora B kinase inhibitors was synthesized and evaluated the anti-proliferative activities against A549, HCT116, MCF-7 and HepG2 cells. 1-(4-(2-((4-Oxo-3,4-dihydrophthalazin-1-yl)amino)ethyl) phenyl)-3-(3-(trifluoromethyl)phenyl)urea (17b) exhibited the most potent anti-proliferative activity against HCT116 cells with IC50 value of 4.35 ± 1.21 μM, as well as the moderate Aurora B inhibitory activity with the IC50 value of 142 nM. Furthermore, 17b inhibited the phosphorylation of Aurora B on Thr232, leading to cell cycle arrest in the G2/M phase by down-regulating the expression of CyclinB1 and Cdc2 proteins, and apoptosis by up-regulating the expression of BAD and Bax proteins in HCT116 cells. In addition, a docking study revealed that 17b could form key hydrogen bonds with Ala173, Glu171 and Glu177 in Aurora B. All the results reveal that 17b is worthy of further development as an Aurora B kinase inhibitor.

Keywords: Antitumor; Apoptosis; Aurora B kinase; Phthalazinones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aurora Kinase B / antagonists & inhibitors*
  • Aurora Kinase B / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Enzyme Assays
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Phosphorylation / drug effects
  • Phthalazines / chemical synthesis
  • Phthalazines / metabolism
  • Phthalazines / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Phthalazines
  • Protein Kinase Inhibitors
  • AURKB protein, human
  • Aurora Kinase B