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

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 var...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-08, Vol.17 (16), p.6123-6136
Main Authors: Foss, Frank W., Mathews, Thomas P., Kharel, Yugesh, Kennedy, Perry C., Snyder, Ashley H., Davis, Michael D., Lynch, Kevin R., Macdonald, Timothy L.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Fingolimod Hydrochloride
FTY-720
Heterocycles
Humans
Immunosuppressive Agents - chemical synthesis
Immunosuppressive Agents - chemistry
Immunosuppressive Agents - pharmacology
Lymphopenia
Lymphopenia - chemically induced
Medical sciences
Mice
Miscellaneous
Pharmacology. Drug treatments
Pro-drugs
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Propanols - chemical synthesis
Propanols - chemistry
Propylene Glycols - chemical synthesis
Propylene Glycols - chemistry
Propylene Glycols - pharmacology
Receptors, Lysosphingolipid - agonists
Receptors, Lysosphingolipid - metabolism
Sphingosine - analogs & derivatives
Sphingosine - chemical synthesis
Sphingosine - chemistry
Sphingosine - pharmacology
Sphingosine-1-phosphate
Structure-Activity Relationship
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Summary: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 (S1P 1–5). Agonism at S1P 1 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 S1P 1 receptor; additionally, the imidazole class of compounds rendered mice lymphopenic.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.04.015