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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Carbolines / chemical synthesis*
-
Carbolines / chemistry
-
Carbolines / pharmacology*
-
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
-
Cyclin-Dependent Kinase 4 / chemistry
-
Drug Design
-
Humans
-
Inhibitory Concentration 50
-
Magnetic Resonance Spectroscopy
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology
-
Spectrometry, Mass, Fast Atom Bombardment
-
Tryptamines / chemical synthesis*
-
Tryptamines / chemistry
-
Tryptamines / pharmacology*
Substances
-
Carbolines
-
Protein Kinase Inhibitors
-
Tryptamines
-
CDK4 protein, human
-
Cyclin-Dependent Kinase 4