Design, Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Selective PI3Kβ Inhibitors

Molecules. 2016 Jul 2;21(7):876. doi: 10.3390/molecules21070876.

Abstract

A novel series of PI3Kβ (Phosphatidylinositol-3-kinases beta subunit) inhibitors with the structure of benzothiazole scaffold have been designed and synthesized. All the compounds have been evaluated for inhibitory activities against PI3Kα, β, γ, δ and mTOR (Mammalian target of rapamycin). Two superior compounds have been further evaluated for the IC50 values against PI3Ks/mTOR. The most promising compound 11 displays excellent anti-proliferative activity and selectivity in multiple cancer cell lines, especially in the prostate cancer cell line. Docking studies indicate the morpholine group in 2-position of benzothiazole is necessary for the potent antitumor activity, which confirms our design is reasonable.

Keywords: PI3Kβ; docking; kinase inhibitor; mTOR.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / chemistry*
  • Benzothiazoles / pharmacology*
  • Binding Sites
  • Cell Line, Tumor
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Phosphatidylinositol 3-Kinases / chemistry*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzothiazoles
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • benzothiazole