2-Deoxy derivative is a partial agonist of the intracellular messenger inositol 3,4,5,6-tetrakisphosphate in the epithelial cell line T84

Marco T. Rudolf, Wen Hong Li, Nora Wolfson, Alexis E. Traynor-Kaplan, Carsten Schultz

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Abstract

We have synthesized the first deoxy analogues of myo-inositol 3,4,5,6- tetrakisphosphate (1) [Ins(3,4,5,6)P4], rac-2-deoxy-myo-inositol 3,4,5,6- tetrakisphosphate (rac-2), 2-deoxy-myo-inositol 1,4,5,6-tetrakisphosphate (ent-2), and rac-1-deoxy-myo-inositol 3,4,5,6-tetrakisphosphate (rac-3). In order to evaluate the binding properties of the three derivatives to the yet unidentified intracellular binding sites for Ins(3,4,5,6)P4, the analogues were converted to membrane-permeant derivatives. Starting with common inositol precursors, various forms of Barton-McCombie deoxygenation and classical protection/deprotection procedures yielded the desired precursors rac-1-O-butyryl-2-deoxy-myo-inositol (rac-12), ent-3-O-butyryl-2-deoxy-myo- inositol (ent-12), and rac-2-O-butyryl-1-deoxy-myo-inositol (rac-19), respectively. Phosphorylation and subsequent deprotection yielded rac-2, ent- 2, and rac-3. Alternatively, phosphorylation followed by alkylation with acetoxymethyl bromide gave the membrane-permeant derivatives 1-O-butyryl-2- deoxy-myo-inositol 3,4,5,6-tetrakisphosphate octakis(acetoxymethyl)ester(rac- 5), 3-O-butyryl-2-deoxy-myo-inositol 1,4,5,6-tetrakisphosphate octakis(acetoxymethyl) ester (ent-5), and 2-O-butyryl-1-deoxy-myo-inositol 3,4,5,6-tetrakisphosphate octakis(acetoxymethyl) ester (rac-6), respectively. We examined the potency of the membrane-permeant deoxy derivatives in inhibition of calcium-mediated chloride secretion (CaMCS) in intact T84 cells. Compared to the 1,2-di-O-butyryl-myo-inositol 3,4,5,6- tetrakisphosphate octakis(acetoxymethyl) ester (4), the membrane-permeant derivative of Ins(3,4,5,6)P4 (1), the 2-deoxy derivative (rac-5) exhibited a slightly weaker inhibitory effect, while the enantiomerically pure 2-deoxy- Ins(1,4,5,6)P4 (ent-5) and the 1-deoxy derivative (rac-6) were inactive. As expected, the effect was stereoselective. Thus, the 1-hydroxyl group is apparently essential for binding and the inhibitory effect of Ins(3,4,5,6)P4 on chloride secretion, whereas the 2-hydroxyl group plays a less important role.

Original languageEnglish (US)
Pages (from-to)3635-3644
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number19
DOIs
StatePublished - Sep 10 1998

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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