Design, synthesis and biological evaluation of new tryptamine and tetrahydro-β-carboline-based selective inhibitors of CDK4

A library of selective inhibitors of CDK4 based on a tryptamine or β-carboline biphenyl carbonyl amides have been synthesised using the Suzuki–Miyaura cross-coupling reaction. The compounds were designed in view an observed π-stacking pocket within the active site of a CDK4 homology model. We presen...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-08, Vol.16 (16), p.7728-7739
Main Authors: Jenkins, Paul R., Wilson, James, Emmerson, Daniel, Garcia, Marcos D., Smith, Matthew R., Gray, Stephen J., Britton, Robert G., Mahale, Sachin, Chaudhuri, Bhabatosh
Format: Article
Language:English
Subjects:
Anti-cancer
Antineoplastic agents
Biological and medical sciences
Carbolines - chemical synthesis
Carbolines - chemistry
Carbolines - pharmacology
CDK4 inhibitors
Cyclin-Dependent Kinase 4 - antagonists & inhibitors
Cyclin-Dependent Kinase 4 - chemistry
Drug Design
Fascaplysin
General aspects
Humans
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Medical sciences
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Spectrometry, Mass, Fast Atom Bombardment
Suzuki–Miyaura reaction
Tryptamines - chemical synthesis
Tryptamines - chemistry
Tryptamines - pharmacology
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Summary:A library of selective inhibitors of CDK4 based on a tryptamine or β-carboline biphenyl carbonyl amides have been synthesised using the Suzuki–Miyaura cross-coupling reaction. The compounds were designed in view an observed π-stacking pocket within the active site of a CDK4 homology model. We present the design, synthesis and biological activity of a library of substituted (biphenylcarbonyl)-tryptamine and (biphenylcarbonyl)-tetrahydro-β-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 μM, three of them containing the para-biphenyl plus para-substituents supporting the existence of a π-stacking pocket within the active site of CDK4.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.07.002