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

Bioorg Med Chem. 2008 Aug 15;16(16):7728-39. doi: 10.1016/j.bmc.2008.07.002.

Paul R Jenkins ¹, James Wilson, Daniel Emmerson, Marcos D Garcia, Matthew R Smith, Stephen J Gray, Robert G Britton, Sachin Mahale, Bhabatosh Chaudhuri

Affiliations

Affiliation

1 Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK. [email protected]

PMID: 18650093 DOI: 10.1016/j.bmc.2008.07.002

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.

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