Synthetic D- and L-enantiomers of 2,2-difluoro-2-deoxy-myo-inositol 1,4,5-trisphosphate interact differently with myo-inositol 1,4,5-trisphosphate binding proteins: identification of a potent small molecule 3-kinase inhibitor.
Abstract |
The ability of two enantiomeric fluoro-analogues of D- myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] to mobilize intracellular Ca2+ stores in SH-SY5Y neuroblastoma cells has been investigated. (-)-D-2,2-difluoro-2-deoxy-myo-Ins(1,4,5)P3 [D-2,2-F2-Ins(1,4,5)P3] was a full agonist [EC50 0.21 microM] and slightly less potent than D-Ins(1,4,5)P3 [EC50 0.13 microM]. (+)-L-2,2-F2Ins(1,4,5)P3 was a very poor agonist, confirming the stereospecificity of the Ins(1,4,5)P3 receptor. D-2,2-F2-Ins(1,4,5)P3 mobilized Ca2+ with broadly similar kinetics to Ins(1,4,5)P3 and was a substrate for Ins(1,4,5)P3 3-kinase inhibiting Ins(1,4,5)P3 phosphorylation (apparent Ki = 10.2 microM) but was recognised less well than Ins(1,4,5)P3. L-2,2-F2-Ins(1,4,5)P3 was a potent competitive inhibitor of 3-kinase (Ki = 11.9 microM). Whereas D-2,2-F2-Ins(1,4,5)P3 was a good substrate for Ins(1,4,5)P3 5-phosphatase, L-2,2-F2Ins(1,4,5)P3 was a relatively potent inhibitor (Ki = 19.0 microM).
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Authors | S T Safrany, D A Sawyer, S R Nahorski, B V Potter |
Journal | Chirality
(Chirality)
Vol. 4
Issue 7
Pg. 415-22
( 1992)
ISSN: 0899-0042 [Print] United States |
PMID | 1334423
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 2,2-difluoro-2-deoxy-inositol 1,4,5-trisphosphate
- Inositol 1,4,5-Trisphosphate
- Phosphotransferases
- Phosphotransferases (Alcohol Group Acceptor)
- Inositol 1,4,5-trisphosphate 3-kinase
- Calcium
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Topics |
- Calcium
(metabolism)
- Humans
- Inositol 1,4,5-Trisphosphate
(analogs & derivatives, chemical synthesis, metabolism, pharmacology)
- Kinetics
- Neuroblastoma
- Phosphotransferases
(antagonists & inhibitors)
- Phosphotransferases (Alcohol Group Acceptor)
- Stereoisomerism
- Structure-Activity Relationship
- Tumor Cells, Cultured
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