Deoxygenated phosphorothioate inositol phosphate analogs: Synthesis, phosphatase stability, and binding affinity

Xiaodan Liu, Emily C. Moody, Stephen S. Hecht, Shana J. Sturla

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Inositol phosphates, such as 1d-myo-Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], are cellular second messengers with potential roles in cancer prevention and therapy. It typically is difficult to attribute specific pharmacological activity to a single inositol phosphate because they are rapidly metabolized by phosphatases and kinases. In this study, we have designed stable analogs of myo-inositol 4,5-bisphosphate [Ins(4,5)P2] and Ins(1,4,5)P3 that retain the cyclohexane scaffold, but lack hydroxyl groups that might be phosphorylated and have phosphate groups replaced with phosphatase-resistant phosphorothioates. An Ins(1,4,5)P3 analog, 1d-2,3-dideoxy-myo-inositol 1,4,5-trisphosphorothioate, was synthesized from (-)-quebrachitol, and an Ins(4,5)P2 analog, 1d-1,2,3-trideoxy-myo-inositol 4,5-bisphosphorothioate, was prepared from cyclohexenol. The Ins(1,4,5)P3 analog was recognized by Ins(1,4,5)P3 receptor with a binding constant (Kd) of 810 nM, compared with 54 nM for the native ligand Ins(1,4,5)P3, and was resistant to dephosphorylation by alkaline phosphatase under conditions in which Ins(1,4,5)P3 is extensively hydrolyzed. Analogs developed in this study are potential chemical probes for understanding mechanisms of inositol phosphate actions that may be elucidated by eliciting specific and prolonged activation of the Ins(1,4,5)P3 receptor.

Original languageEnglish (US)
Pages (from-to)3419-3427
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number6
DOIs
StatePublished - Mar 15 2008

Keywords

  • Binding affinity
  • Ins(1,4,5)P analog
  • Ins(1,4,5)P receptor
  • Myo-inositol 1,4,5-trisphosphate
  • Phosphatase-stable analogs

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