title: Potent inhibitors of phosphatidylinositol 3 (PI3) kinase that have antiproliferative activity only when delivered as prodrug forms.
abstract: Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl-substituted analogues were further derivatized as prodrugs resulting in restoration of cell-based activity. These data provide a conceptual model for development of tumor-targeting prodrug forms of cell-impermeable PI3K inhibitors.
authors.affiliation: Department of Chemistry, La Trobe University Institute for Molecular Science, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: O'Brien
authors.forename: Syazwani
authors.initials: S
authors.lastname: Amran
authors.forename: Jelena
authors.initials: J
authors.lastname: Medan
authors.forename: Ben
authors.initials: B
authors.lastname: Cleary
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Deady
authors.forename: Ian G
authors.initials: IG
authors.lastname: Jennings
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.forename: Belinda M
authors.initials: BM
authors.lastname: Abbott
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one