Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors

Eur J Med Chem. 2020 Nov 15:206:112713. doi: 10.1016/j.ejmech.2020.112713. Epub 2020 Aug 8.

Abstract

Sphingosine kinase (SphK) is primarily responsible for the production of Sphingosine-1-phosphate (S1P) that plays an important role in many biological and pathobiological processes including cancer, inflammation, neurological and cardiovascular disorders. Most research has focused on developing inhibitors of SphK1 rather than inhibitors of the other isoform SphK2 which has great importance in several pathophysiologic pathways. Exploration of new analogues for improving the potency and selectivity of SphK2 inhibitors is critical. We now have designed, synthesized, and evaluated eighteen new 1,2,3-triazole analogues for their SphK2 inhibitory activity using a ADP-Glo kinase assay, and explored their in vivo anti-tumor bioactivity. Several compounds including 21c, 21e, 21g, 25e-h, 29a-c have high selectivity for SphK2 over SphK1; compound 21g displayed the highest potency with an IC50 value of 0.23 μM. In addition, three compounds 21a, 21b, and 25b have high anti-tumor activity against U-251 MG human glioblastoma cells. Molecular modeling study was performed to elucidate the polar head group and 1,2,3-triazole pharmacophore impact on the SphK2 selectivity.

Keywords: 1,2,3-Triazole hybrids; ADP-Glo; Molecular docking; Selectivity; Sphingosine kinase 2 inhibitors; U-251 MG Human glioblastoma cell.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Molecular Docking Simulation
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Conformation
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry*
  • Triazoles / metabolism
  • Triazoles / pharmacology*

Substances

  • Antineoplastic Agents
  • Triazoles
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase 2, human