Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs

Frank W. Foss, Thomas P. Mathews, Yugesh Kharel, Perry C. Kennedy, Ashley H. Snyder, Michael D. Davis, Kevin R. Lynch, Timothy L. Macdonald

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

In the search for bioactive sphingosine 1-phosphate (S1P) receptor ligands, a series of 2-amino-2-heterocyclic-propanols were synthesized. These molecules were discovered to be substrates of human-sphingosine kinases 1 and 2 (SPHK1 and SPHK2). When phosphorylated, the resultant phosphates showed varied activities at the five sphingosine-1-phosphate (S1P) receptors (S1P1-5). Agonism at S1P1 was displayed in vivo by induction of lymphopenia. A stereochemical preference of the quaternary carbon was crucial for phosphorylation by the kinases and alters binding affinities at the S1P receptors. Oxazole and oxadiazole compounds are superior kinase substrates to FTY720, the prototypical prodrug immunomodulator, fingolimod (FTY720). The oxazole-derived structure was the most active for human SPHK2. Imidazole analogues were less active substrates for SPHKs, but more potent and selective agonists of the S1P1 receptor; additionally, the imidazole class of compounds rendered mice lymphopenic.

Original languageEnglish (US)
Pages (from-to)6123-6136
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number16
DOIs
StatePublished - Aug 15 2009
Externally publishedYes

Keywords

  • FTY-720
  • Heterocycles
  • Lymphopenia
  • Pro-drugs
  • Sphingosine-1-phosphate
  • Structure-activity-relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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