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Synthesis 2012(1): 69-82  
DOI: 10.1055/s-0031-1289613
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Convenient Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines Possessing Biological Activity

Maud Antoinea, Matthias Gerlachb, Eckhard Güntherb, Tilmann Schusterb, Michael Czechb, Irene Seipeltb, Pascal Marchand*a
a Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections, de l’Immunité et du Cancer, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France
Fax: +33(2)40412876; e-Mail: pascal.marchand@univ-nantes.fr;
b Æterna Zentaris GmbH, Weismuellerstr. 50, 60314 Frankfurt/Main, Germany
Further Information

Publication History

Received 22 September 2011
Publication Date:
18 November 2011 (online)

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Abstract

A regioselective synthetic route to 2,8-disubstituted pyrido[3,4-b]pyrazines, by initial condensation reaction between suitable diaminopyridines and α-keto aldehydes equivalents, has been developed. Focusing on the functionalization on C-8, 2-aryl-8-bromo- and 8-amino-2-arylpyrido[3,4-b]pyrazines have been synthesized. Anilines, amides, and ureas have been introduced at the 8-position from key intermediates. 2,8-Disubstituted pyrido[3,4-b]pyrazines thus prepared were found to be of biological interest.

Key words

pyrido[3,4-b]pyrazines - pyridines - thioacetals - phenylglyoxals - regioselectivity - condensation

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Kinase Inhibition Assay: Recombinant kinases were purchased from Millipore or ProQinase. AlphaScreen Bead Kits from Perkin-Elmer were used to quantify the kinase activity. For the assessment of IC50 values, compounds were tested at 10 final concentrations between 3.16 nM and 100 µM. Kinase, 10 µM ATP, kinase substrate, and the test compound were incubated for 1 h on a 384-well Optiplate in a final volume of 15 µl. The kinase reaction was stopped by adding 10 µl ALPHA-Beadmix. The read out was done on the next morning using an Envision reader (PerkinElmer). IC50 values were calculated using Graph Pad Prism software.