Synthesis, Protein Kinase Inhibitory Potencies, and in Vitro Antiproliferative Activities of Meridianin Derivatives

• DOI: 10.1021/jm200464w
• Publication Date: 2011-05-30T14:08:38Z
• Authors: Francis Giraud; Georges Alves; Eric Debiton; Lionel Nauton; Vincent Théry; Emilie Durieu; Yoan Ferandin; Olivier Lozach; Laurent Meijer; Fabrice Anizon; Elisabeth Pereira; Pascale Moreau
• Keywords: Models, Molecular; 0303 health sciences; Binding Sites; Antineoplastic Agents; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Indole Alkaloids; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; Adenosine Triphosphate; Cell Line, Tumor; Animals; Humans; Drug Screening Assays, Antitumor; Cells, Cultured; Cell Proliferation

The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as well as some of their synthetic intermediates were tested for their kinase inhibitory potencies and for their in vitro antiproliferative activities. We found that this series of compounds is particularly interesting in the development of new inhibitors of DYRK1A and CLK1 kinases. The most effective compounds toward these two kinase families are the 6- and 7-bromo derivatives 30, 33, and 34 that showed more than 45-fold selectivity toward DYRK1A/CLK1 kinases over the other kinases tested. Meridianin derivatives could thus be developed toward potent and selective inhibitors of key RNA splicing regulators and potential therapeutic agents.