Synthesis of novel 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases

The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6784-6788
Hauptverfasser:	Deau, Emmanuel, Loidreau, Yvonnick, Marchand, Pascal, Nourrisson, Marie-Renée, Loaëc, Nadège, Meijer, Laurent, Levacher, Vincent, Besson, Thierry
Format:	Artikel
Sprache:	eng
Schlagworte:	Amines - chemical synthesis Amines - chemistry Amines - metabolism Amines - pharmacology Catalysis Chemical Sciences chemistry Cyclin-dependent kinase 5 Cyclization Dimroth rearrangement Enzyme Activation - drug effects Formamide degradation Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - metabolism Heterocyclic Compounds, 3-Ring - pharmacology inhibitory concentration 50 microwave treatment Microwave-assisted chemistry Microwaves Organic chemistry Palladium - chemistry phosphotransferases (kinases) Protein Binding - drug effects Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Pyridines - chemistry Pyrimidines - chemistry Serine/threonine kinases inhibitors Structure-Activity Relationship Suzuki–Miyaura cross-coupling
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Zusammenfassung:	The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC50 value of 49nM and proved to be specific to CLK1 among the panel of tested kinases.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.10.019