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. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Bioorganic and Medicinal Chemistry Letters Année : 2013

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.

Yvonnick Loidreau
  • Fonction : Auteur
Pascal Marchand
  • Fonction : Auteur
Marie-Renée Nourrisson
  • Fonction : Auteur
Nadège Loaëc
Laurent Meijer
  • Fonction : Auteur
Thierry Besson

Résumé

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 49 nM and proved to be specific to CLK1 among the panel of tested kinases.

Domaines

Chimie organique

Dates et versions

hal-00997420 , version 1 (28-05-2014)

Identifiants

Citer

Emmanuel Deau, Yvonnick Loidreau, Pascal Marchand, Marie-Renée Nourrisson, Nadège Loaëc, et al.. 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.. Bioorganic and Medicinal Chemistry Letters, 2013, 23 (24), pp.6784-6788. ⟨10.1016/j.bmcl.2013.10.019⟩. ⟨hal-00997420⟩
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