TY - JOUR
T1 - 2-Deoxy derivative is a partial agonist of the intracellular messenger inositol 3,4,5,6-tetrakisphosphate in the epithelial cell line T84
AU - Rudolf, Marco T.
AU - Li, Wen Hong
AU - Wolfson, Nora
AU - Traynor-Kaplan, Alexis E.
AU - Schultz, Carsten
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1998/9/10
Y1 - 1998/9/10
N2 - 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.
AB - 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.
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U2 - 10.1021/jm970781n
DO - 10.1021/jm970781n
M3 - Article
C2 - 9733488
AN - SCOPUS:0032505135
SN - 0022-2623
VL - 41
SP - 3635
EP - 3644
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -