title: Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors.
abstract: PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald-Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed.
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, VIC 3086, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: O'Brien
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, VIC 3086, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Brzozowski
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, VIC 3086, Australia.
authors.forename: David J D
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, VIC 3086, Australia.
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Deady
authors.affiliation: Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, VIC 3086, Australia. Electronic address: b.abbott@latrobe.edu.au.
authors.forename: Belinda M
authors.initials: BM
authors.lastname: Abbott
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D064413:3-Phosphoinositide-Dependent Protein Kinases
keywords: 3-Anilino-quinolin-2(1H)-ones; 3-Phosphoinositide-dependent kinase 1 (PDK1); Buchwald–Hartwig cross-coupling; Cross-coupling; Inhibitor