Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex

J Med Chem. 2008 Feb 28;51(4):737-51. doi: 10.1021/jm700940h. Epub 2008 Jan 31.


We report the synthesis and biological characterization of 3-(pyrimidin-4-yl)-7-azaindoles (meriolins), a chemical hybrid between the natural products meridianins and variolins, derived from marine organisms. Meriolins display potent inhibitory activities toward cyclin-dependent kinases (CDKs) and, to a lesser extent, other kinases (GSK-3, DYRK1A). The crystal structures of 1e (meriolin 5) and variolin B (Bettayeb, K.; Tirado, O. M.; Marionneau-Lambert, S.; Ferandin, Y.; Lozach, O.; Morris, J.; Mateo-Lozano, S.; Drückes, P.; Schächtele, C.; Kubbutat, M.; Liger, F.; Marquet, B.; Joseph, B.; Echalier, A.; Endicott, J.; Notario, V.; Meijer, L. Cancer Res. 2007, 67, 8325-8334) in complex with CDK2/cyclin A reveal that the two inhibitors are orientated in very different ways inside the ATP-binding pocket of the kinase. A structure-activity relationship provides further insight into the molecular mechanism of action of this family of kinase inhibitors. Meriolins are also potent antiproliferative and proapoptotic agents in cells cultured either as monolayers or in spheroids. Proapoptotic efficacy of meriolins correlates best with their CDK2 and CDK9 inhibitory activity. Meriolins thus constitute a promising class of pharmacological agents to be further evaluated against the numerous human diseases that imply abnormal regulation of CDKs including cancers, neurodegenerative disorders, and polycystic kidney disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Crystallization
  • Crystallography, X-Ray
  • Cyclin A / chemistry*
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / chemistry*
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / chemistry
  • Drug Screening Assays, Antitumor
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Models, Molecular
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Spheroids, Cellular / drug effects
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Aza Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclin A
  • Indoles
  • Pyrimidines
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 9

Associated data

  • PDB/3BHT
  • PDB/3BHU
  • PDB/3BHV