title: Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4.
abstract: We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-beta-carboline compounds related to the natural product fascaplysin, as novel inhibitors of CDK4/cyclin D1. We show all these molecules, prepared using the Suzuki-Miyaura reaction, being selective inhibitors of CDK4 over CDK2. The most active compounds have a CDK4 IC(50) in the range 9-11 microM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a pi-stacking pocket within the active site of CDK4.
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK. kin@leicester.ac.uk
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jenkins
authors.forename: James
authors.initials: J
authors.lastname: Wilson
authors.forename: Daniel
authors.initials: D
authors.lastname: Emmerson
authors.forename: Marcos D
authors.initials: MD
authors.lastname: Garcia
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gray
authors.forename: Robert G
authors.initials: RG
authors.lastname: Britton
authors.forename: Sachin
authors.initials: S
authors.lastname: Mahale
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014363:Tryptamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002243:Carbolines; D047428:Protein Kinase Inhibitors; D014363:Tryptamines; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4