title: Synthesis, protein kinase inhibitory potencies, and in vitro antiproliferative activities of meridianin derivatives.
abstract: 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.
authors.affiliation: Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, BP 10448, Clermont-Ferrand, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Giraud
authors.forename: Georges
authors.initials: G
authors.lastname: Alves
authors.forename: Eric
authors.initials: E
authors.lastname: Debiton
authors.forename: Lionel
authors.initials: L
authors.lastname: Nauton
authors.forename: Vincent
authors.initials: V
authors.lastname: Théry
authors.forename: Emilie
authors.initials: E
authors.lastname: Durieu
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pereira
authors.forename: Pascale
authors.initials: P
authors.lastname: Moreau
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D026121:Indole Alkaloids; C560347:meridianin A; C522700:meridianin F; C522699:meridianin G; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases