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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
Author(s) -
Safrany Stephen T.,
Sawyer Deborah A.,
Nahorski Stefan R.,
Potter Barry V.L.
Publication year - 1992
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530040703
Subject(s) - chemistry , inositol , stereochemistry , stereospecificity , enantiomer , agonist , receptor , kinase , substrate (aquarium) , biochemistry , catalysis , oceanography , geology
The ability of two enantiomeric fluoro‐analogues of D ‐ myo ‐inositol 1,4,5‐trisphosphate [Ins(1,4,5)P 3 ] to mobilize intracellular Ca 2+ stores in SH‐SY5Y neuroblastoma cells has been investigated. (—)‐ D ‐2,2‐difluoro‐2‐deoxy‐ myo ‐Ins(1,4,5)P 3 [ D ‐2,2‐F 2 ‐Ins(1,4,5)P 3 ] was a full agonist [EC 50 0.21 μ M ] and slightly less potent than D ‐Ins(1,4,5)P 3 [EC 50 0.13 μ M ]. (+)‐ L ‐2,2‐F 2 Ins(1,4,5)P 3 was a very poor agonist, confirming the stereospecificity of the Ins(1,4,5)P 3 receptor. D ‐2,2‐F 2 ‐Ins(1,4,5)P 3 mobilized Ca 2+ with broadly similar kinetics to Ins(1,4,5)P 3 and was a substrate for Ins(1,4,5)P 3 3‐kinase inhibiting Ins(1,4,5)P 3 phosphorylation (apparent K i = 10.2 μ M ) but was recognised less well than Ins(1,4,5)P 3 . L ‐2,2‐F 2 ‐Ins(1,4,5)P 3 was a potent competitive inhibitor of 3‐kinase ( K i = 11.9 μ M ). Whereas D ‐2,2‐F 2 ‐Ins(1,4,5)P 3 was a good substrate for Ins(1,4,5)P 3 5‐phosphatase, L ‐2,2‐F 2 Ins(1,4,5)P 3 was a relatively potent inhibitor ( K i = 19.0 μ M ). © 1992 Wiley‐Liss, Inc.