title: Synthesis and biological activity of PTEN-resistant analogues of phosphatidylinositol 3,4,5-trisphosphate.
abstract: The activation of phosphatidylinositol 3-kinase (PI 3-K) and subsequent production of PtdIns(3,4,5)P3 launches a signal transduction cascade that impinges on a plethora of downstream effects on cell physiology. Control of PI 3-K and PtdIns(3,4,5)P3 levels is an important therapeutic target in treatments for allergy, inflammation, cardiovascular, and malignant human diseases. We designed metabolically stabilized, that is, phosphatase resistant, analogues of PtdIns(3,4,5)P3 as probes for long-lived potential agonists or potential antagonists for cellular events mediated by PtdIns(3,4,5)P3. In particular, two types of analogues were prepared containing phosphomimetics that would be selectively resistant to the lipid 3-phosphatase PTEN. The total asymmetric synthesis of the 3-phosphorothioate-PtdIns(3,4,5)P3 and 3-methylenephosphonate-PtdIns(3,4,5)P3 analogues is described. These two analogues showed differential binding to PtdIns(3,4,5)P3 binding modules, and both were potential long-lived activators that mimicked insulin action in sodium transport in A6 cells.
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA.
authors.forename: Honglu
authors.initials: H
authors.lastname: Zhang
authors.forename: Nicolas
authors.initials: N
authors.lastname: Markadieu
authors.forename: Renaud
authors.initials: R
authors.lastname: Beauwens
authors.forename: Christophe
authors.initials: C
authors.lastname: Erneux
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D010710:Phosphates / Q000737:chemistry; D018129:Phosphatidylinositol Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010710:Phosphates; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; C083120:phosphorodithioic acid; D051059:PTEN Phosphohydrolase