title: Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolin complex.
abstract: 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.
authors.affiliation: Laboratory of Molecular Biophysics, Department of Biochemistry, The Rex Richards Building, University of Oxford, UK.
authors.forename: Aude
authors.initials: A
authors.lastname: Echalier
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Monique
authors.initials: M
authors.lastname: Clément
authors.forename: Annie
authors.initials: A
authors.lastname: Valette
authors.forename: François
authors.initials: F
authors.lastname: Liger
authors.forename: Bernard
authors.initials: B
authors.lastname: Marquet
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Morris
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003460:Crystallization; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019925:Cyclin A; D007211:Indoles; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9