title: 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.
abstract: 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.
authors.affiliation: Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Deau
authors.forename: Yvonnick
authors.initials: Y
authors.lastname: Loidreau
authors.forename: Pascal
authors.initials: P
authors.lastname: Marchand
authors.forename: Marie-Renée
authors.initials: MR
authors.lastname: Nourrisson
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Vincent
authors.initials: V
authors.lastname: Levacher
authors.forename: Thierry
authors.initials: T
authors.lastname: Besson
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002384:Catalysis; D003500:Cyclization; D004789:Enzyme Activation / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008872:Microwaves; D010165:Palladium / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C500447:3,5-dibromopyridine; C000589841:7-(2,4-dichlorophenyl)pyrido(2',3'-4,5)furo(3,2-d)pyrimidin-4-amine; D000588:Amines; D006575:Heterocyclic Compounds, 3-Ring; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D010165:Palladium; D017346:Protein Serine-Threonine Kinases; C030986:pyrimidine
keywords: Dimroth rearrangement; Formamide degradation; Microwave-assisted chemistry; Serine/threonine kinases inhibitors; Suzuki–Miyaura cross-coupling