title: Synthesis, crystal structure and biological activity of beta-carboline based selective CDK4-cyclin D1 inhibitors.
abstract: The design, synthesis and biological activity of a series of non-planar dihydro-beta-carboline and beta-carboline-based derivatives of the toxic anticancer agent fascaplysin is presented. We show these compounds to be selective inhibitors of CDK4 over CDK2 with an IC50 (CDK4-cyclin D1) = 11 micromol for the best compound in the series 4d. The crystallographic analysis of some of the compounds synthesised (3b/d and 4a-d) was carried out, in an effort to estimate the structural similarities between the designed inhibitors and the model compound fascaplysin.
authors.affiliation: Department of Chemistry, University of Leicester, Leicester, UKLE1 7RH.
authors.forename: Marcos D
authors.initials: MD
authors.lastname: García
authors.forename: A James
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Daniel P G
authors.initials: DP
authors.lastname: Emmerson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jenkins
authors.forename: Sachin
authors.initials: S
authors.lastname: Mahale
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D000644:Quaternary Ammonium Compounds; D007212:Indolizines
chemical_list: D002243:Carbolines; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D004791:Enzyme Inhibitors; D007211:Indoles; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D007212:Indolizines