title: Design and Synthesis of Coumarin Derivatives as Novel PI3K Inhibitors.
abstract: BACKGROUND
  Coumarins possess a broad spectrum of biological activities and are important pharmacophores in drug developments. Since aberrant upregulation of PI3K/Akt signaling is related to uncontrolled tumor cell proliferation, enhanced migration, and adhesion-independent tumor growth, it is of interests to find novel coumarin derivatives as anticancer agents targeting the PI3K/Akt signaling pathway.
  
  
  OBJECTIVE
  A variety of coumarin derivatives possessing the pyridinylurea units were designed to increase their potency and isoform selectivity against PI3Ks.
  
  
  METHODS
  Novel coumarin analogs 4a-m were were prepared from 5-methylpyridin-2-ylamine in a straightforward way and their growth inhibitory activity against tumor cells was evaluated by a MTT assay. The inhibitory activity against PI3Kα, β, δ and γ was measured by luminescent assay. Akt phosphorylation inhibition and caspase 3 and PARP activation were measured by Western blot analysis. Apoptosis was measured by staining cells with annexin V-FITC and 7-AAD.
  
  
  RESULTS
  In general, these coumarin analogs exhibited good in vitro growth inhibitory activities against tumor K562, Hela, A549 and MCF-7 cells. Some of them showed comparable or better potency than BENC-511. Compounds 4b and 4h were much more potent PI3K inhibitors than S14161 or BENC-511. In addition, 4b was more selective to PI3Kα/β over PI3Kδ/γ, while 4h was a selective PI3Kα/β/δ inhibitor. Moreover, 4h could suppress the phosphorylation of Akt and induce K562 cell apoptosis.
  
  
  CONCLUSIONS
  Coumarin derivatives possessing the pyridinylurea units are potential PI3K inhibitors and anticancer agents. These findings will be helpful for the future design of more potent and selective PI3K inhibitors.
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Ma
authors.affiliation: Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Zhao-Peng
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases
keywords: Anticancer agents; Friedel-Crafts alkylation; PI3K; PI3K/Akt signal pathway; Pechman reaction; apoptosis; coumarins; inhibitors