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

Abstract
Inositol phosphates, such as 1D-myo-Inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)], 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)P(2)] and Ins(1,4,5)P(3) 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)P(3) analog, 1D-2,3-dideoxy-myo-inositol 1,4,5-trisphosphorothioate, was synthesized from (-)-quebrachitol, and an Ins(4,5)P(2) analog, 1D-1,2,3-trideoxy-myo-inositol 4,5-bisphosphorothioate, was prepared from cyclohexenol. The Ins(1,4,5)P(3) analog was recognized by Ins(1,4,5)P(3) receptor with a binding constant (K(d)) of 810 nM, compared with 54 nM for the native ligand Ins(1,4,5)P(3), and was resistant to dephosphorylation by alkaline phosphatase under conditions in which Ins(1,4,5)P(3) 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)P(3) receptor.
AuthorsXiaodan Liu, Emily C Moody, Stephen S Hecht, Shana J Sturla
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 6 Pg. 3419-27 (Mar 15 2008) ISSN: 1464-3391 [Electronic] England
PMID17981044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol Phosphates
  • Phosphates
  • Inositol 1,4,5-Trisphosphate
  • Alkaline Phosphatase
  • thiophosphoric acid
Topics
  • Alkaline Phosphatase (metabolism)
  • Animals
  • Drug Stability
  • Humans
  • Inositol 1,4,5-Trisphosphate (analogs & derivatives, chemistry)
  • Inositol 1,4,5-Trisphosphate Receptors (metabolism)
  • Inositol Phosphates (chemistry)
  • Phosphates
  • Protein Binding

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