Synthesis of Novel FTY720 Analogs with Anticancer Activity through PP2A Activation

  • Molecules. 2018 Oct 24;23(11):2750. doi: 10.3390/molecules23112750.
Jitendra Shrestha  1 ,  Sung Hwan Ki  2 ,  Sang Mi Shin  3 ,  Seon Woong Kim  4 ,  Joo-Youn Lee  5  6 ,  Hee-Sook Jun  7  8 ,  Taeho Lee  9 ,  Sanghee Kim  10 ,  Dong Jae Baek  11 ,  Eun-Young Park  12
Affiliations
  • 1. College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea. [email protected].
  • 2. College of Pharmacy, Chosun University, Gwangju, 61452, Korea. [email protected].
  • 3. College of Pharmacy, Chosun University, Gwangju, 61452, Korea. [email protected].
  • 4. College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea. [email protected].
  • 5. College of Pharmacy, Seoul National University, Seoul 08826, Korea. [email protected].
  • 6. Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. [email protected].
  • 7. Lee Gil Ya Cancer and Diabetes Institute, Department of Molecular Medicine, Gachon University, Incheon 21999, Korea. [email protected].
  • 8. College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 21936, Korea. [email protected].
  • 9. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. [email protected].
  • 10. College of Pharmacy, Seoul National University, Seoul 08826, Korea. [email protected].
  • 11. College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea. [email protected].
  • 12. College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea. [email protected].
PMID: 30355990 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.
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