Synthesis, crystal structure and biological activity of beta-carboline based selective CDK4-cyclin D1 inhibitors

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...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2006-01, Vol.4 (24), p.4478-4484
Main Authors: García, Marcos D, Wilson, A James, Emmerson, Daniel P G, Jenkins, Paul R, Mahale, Sachin, Chaudhuri, Bhabatosh
Format: Article
Language:English
Subjects:
Carbolines - chemistry
Carbolines - pharmacology
Crystallography, X-Ray
Cyclin D1 - antagonists & inhibitors
Cyclin-Dependent Kinase 4 - antagonists & inhibitors
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Indoles - chemistry
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
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Summary: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.
ISSN:1477-0520
1477-0539
DOI:10.1039/b613861f