Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators

Liu, Zheng and MacRitchie, Neil and Pyne, Susan and Pyne, Nigel J and Bittman, Robert (2013) Synthesis of (S)-FTY720 vinylphosphonate analogues and evaluation of their potential as sphingosine kinase 1 inhibitors and activators. Bioorganic and Medicinal Chemistry, 21 (9). pp. 2503-2510. ISSN 0968-0896 (https://doi.org/10.1016/j.bmc.2013.02.042)

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Abstract

Sphingosine kinase 1 (SK1) is over-expressed in many cancers where it provides a selective growth and survival advantage to these cells. SK1 is thus a target for anti-cancer agents that can promote apoptosis of cancer cells. In previous work, we synthesized a novel allosteric SK1 inhibitor, (S)-FTY720 vinylphosphonate. We now report a more expeditious route to this inhibitor which features B-alkyl Suzuki coupling as a key step and show that replacement of the amino group in (S)-FTY720 vinylphosphonate with an azido group converts the vinylphosphonate from an allosteric inhibitor to an activator of SK1 at low micromolar concentrations. Our results demonstrate the feasibility of using the (S)-FTY720 vinylphosphonate scaffold to define structure-activity relationships in the allosteric site of SK1.

ORCID iDs

Liu, Zheng, MacRitchie, Neil, Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584, Pyne, Nigel J ORCID logoORCID: https://orcid.org/0000-0002-5657-4578 and Bittman, Robert;
  • Item type:Article
    ID code:49236
    Dates:
    Date
    Event
    1 May 2013
    Published
    Keywords:cells, cultured, dose-response relationship, drug , HEK293 cells, humans, molecular structure, organophosphonates, phosphotransferases (alcohol group acceptor), protein kinase Inhibitors, structure-activity relationship, Chemistry, Medicine(all), SDG 3 - Good Health and Well-being
    Subjects:Science > Chemistry
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:15 Sep 2014 11:38
    Last modified:30 Sep 2022 01:26
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/49236
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