Synthesis of Novel FTY720 Analogs with Anticancer Activity through PP2A Activation

Molecules. 2018 Oct 24;23(11):2750. doi: 10.3390/molecules23112750.

Abstract

FTY720 inhibits various cancers through PP2A activation. The structure of FTY720 is also used as a basic structure for the design of sphingosine kinase (SK) inhibitors. We have synthesized derivatives using an amide chain in FTY720 with a phenyl backbone, and then compounds were screened by an MTT cell viability assay. The PP2A activity of compound 7 was examined. The phosphorylation levels of AKT and ERK, downstream targets of PP2A, in the presence of compound 7, were determined. Compound 7 may exhibit anticancer effects through PP2A activation rather than the mechanism by inhibition of SK1 in cancer cells. In the docking study of compound 7 and PP2A, the amide chain of compound 7 showed an interaction with Asn61 that was different from FTY720, which is expected to affect the activity of the compound.

Keywords: FTY720; colorectal cancer; derivative; protein phosphatase 2A; sphingosine kinase.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fingolimod Hydrochloride / analogs & derivatives
  • Fingolimod Hydrochloride / chemical synthesis*
  • Fingolimod Hydrochloride / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Phosphorylation
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Phosphatase 2
  • Fingolimod Hydrochloride