title: Synthesis and activity of C11-modified wortmannin probes for PI3 kinase.
abstract: The key role played by PI3 kinase in cancer, hormone action, and a host of other biological functions suggests that specific inhibitors whose disposition could be ascertained in vivo would be useful in biological research or, potentially, for imaging PI3K in a clinical setting. Wortmannin (Wm, 1) is an inhibitor of PI3 kinase with high specificity for this enzyme. We synthesized three modified Wm probes, a biotinylated Wm (7a), a 4-hydroxy-3-iodophenylated Wm, which was obtained both unlabeled (7b) and labeled with (125)I (8), and a fluoresceinated Wm (7c), through modification at C-11, and evaluated their inhibitive activity as inhibitors of PI3 kinase. Biotinylated (7a) and 4-hydroxy-3-iodophenylated Wm's (7b) had IC(50)s for PI3K of 6.11 and 11.02 nM, respectively, compared to an IC(50) for Wm of 1.63 nM. Fluoresceinated Wm (7c) lost considerably more activity than the other derivatives, with an IC(50) of 64.9 nM. The (125)I labeled 4-hydroxy-3-iodophenylated Wm (8) could be detected after reaction with an immunoprecipitate of PI3 kinase. The activity of these reporter Wm's is discussed in relationship to earlier findings on the pharmacological activity of Wm derivatives and the ability of inhibitors to fit into the ATP pocket of PI3 kinase.
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02129, USA.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yuan
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.forename: Seth
authors.initials: S
authors.lastname: Field
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Lewis
authors.initials: L
authors.lastname: Cantley
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
mesh_terms: D000730:Androstadienes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D019793:Fluorescein / Q000737:chemistry; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D019793:Fluorescein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D000077191:Wortmannin