ChemBioChem, 2005, 6, 3, 541-549.
Conrad Kunick, Prof. 1 *, Zhihong Zeng, Dr. 2,
Rick Gussio, Dr. 3, Daniel Zaharevitz, Dr. 3, Maryse Leost 4, Frank Totzke,
Dr. 5, Christoph Schächtele, Dr. 5, Michael H. G. Kubbutat, Dr. 5, Laurent
Meijer, Prof. 4, Thomas Lemcke, Dr. 2
1Institut für Pharmazeutische Chemie,
Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig,
Germany, Fax: (+49) 531-391-2799
2Institut für Pharmazie, Universität Hamburg, Bundesstraße 45, 20146
Hamburg, Germany
3Developmental Therapeutics Program, Division of Cancer Treatment and
Diagnosis, National Cancer Institute, Rockville, Maryland 20852, USA
4Centre National de la Recherche Scientifique, Station Biologique, B. P. 74,
29682 Roscoff, France
5ProQinase GmbH, Breisacher Straße 117, 79106 Freiburg, Germany
email: Prof. Conrad Kunick
*Correspondence to Conrad Kunick, Institut für Pharmazeutische Chemie,
Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig,
Germany, Fax: (+49) 531-391-2799
Keywords:enzymes • inhibitors • lactams
• molecular modeling • paullones • proteins
In order to perform computer-aided design of novel alsterpaullone
derivatives, the vicinity of the entrance to the ATP-binding site was
scanned for areas that could be useful as anchoring points for additional
protein-ligand interactions. Based on the alignment of alsterpaullone in a
CDK1/cyclin B homology model, substituents were attached to the 2-position
of the parent scaffold to enable contacts within the identified areas.
Synthesis of the designed structures revealed three derivatives (3-5) with
kinase-inhibitory activity similar to alsterpaullone. The novel
2-cyanoethylalsterpaullone (7) proved to be the most potent paullone
described so far, exhibiting inhibitory concentrations for CDK1/ cyclin B
and GSK-3 in the picomolar range.
Full article available at http://www3.interscience.wiley.com >>
|
