Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors

Dong Jae Baek, Neil MacRitchie, Nahoum G Anthony, Simon P Mackay, Susan Pyne, Nigel J Pyne, Robert Bittman

Research output: Contribution to journalArticle

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Abstract

The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.

Original languageEnglish
Pages (from-to)9310-9327
Number of pages18
JournalJournal of Medicinal Chemistry
Volume56
Issue number22
DOIs
Publication statusPublished - 27 Nov 2013

Fingerprint

Structure-Activity Relationship
Protein Isoforms
Phosphorylation
Pharmacology
Lipids
sphingosine kinase
1-(4-octylphenethyl)piperidin-4-ol

Keywords

  • benzamides
  • enzyme inhibitors
  • humans
  • hydrophobic and hydrophilic Interactions
  • models, molecular
  • Phosphotransferases (Alcohol Group Acceptor)
  • piperidines
  • protein conformation
  • quaternary ammonium compounds
  • structure-activity relationship
  • triazoles

Cite this

Baek, Dong Jae ; MacRitchie, Neil ; Anthony, Nahoum G ; Mackay, Simon P ; Pyne, Susan ; Pyne, Nigel J ; Bittman, Robert. / Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 22. pp. 9310-9327.
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Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors. / Baek, Dong Jae; MacRitchie, Neil; Anthony, Nahoum G; Mackay, Simon P; Pyne, Susan; Pyne, Nigel J; Bittman, Robert.

In: Journal of Medicinal Chemistry, Vol. 56, No. 22, 27.11.2013, p. 9310-9327.

Research output: Contribution to journalArticle

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AU - Baek, Dong Jae

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AU - Anthony, Nahoum G

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AU - Bittman, Robert

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