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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).
AuthorsS T Safrany, D A Sawyer, S R Nahorski, B V Potter
JournalChirality (Chirality) Vol. 4 Issue 7 Pg. 415-22 ( 1992) ISSN: 0899-0042 [Print] United States
PMID1334423 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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
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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