Design, synthesis and biological evaluation of new tryptamine and tetrahydro-beta-carboline-based selective inhibitors of CDK4.
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.
Jenkins
Paul R
PR
Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK. kin@leicester.ac.uk
Wilson
James
J
Emmerson
Daniel
D
Garcia
Marcos D
MD
Smith
Matthew R
MR
Gray
Stephen J
SJ
Britton
Robert G
RG
Mahale
Sachin
S
Chaudhuri
Bhabatosh
B
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*
D002243:Carbolines; D047428:Protein Kinase Inhibitors; D014363:Tryptamines; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4