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
- 1 January 1992
- Vol. 4 (7) , 415-422
- https://doi.org/10.1002/chir.530040703
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 μM] and slightly less potent than D‐Ins(1,4,5)P3 [EC50 0.13 μM]. (+)‐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 μM) 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 μM). 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 μM).Keywords
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