title: Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(Phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents.
abstract: We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the 3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the V-shaped family were in the micromolar range. Kinase assays were conducted and showed that compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 μM). Compound 11 was also found to be the most potent compound in the series and was identified as a new lead for DYRK1A inhibitor discovery (IC(50) = 60 nM). Docking studies were carried out in order to investigate the inhibition of DYRK1A.
authors.affiliation: Institut de Chimie Organique et Analytique, Université d'Orléans, CNRS UMR 6005, BP 6759, 45067 Orléans Cedex 2, France.
authors.forename: Pamela
authors.initials: P
authors.lastname: Kassis
authors.forename: Joanna
authors.initials: J
authors.lastname: Brzeszcz
authors.forename: Valérie
authors.initials: V
authors.lastname: Bénéteau
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Rémi
authors.initials: R
authors.lastname: Le Guével
authors.forename: Christiane
authors.initials: C
authors.lastname: Guillouzo
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Lewiński
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourg
authors.forename: Lionel
authors.initials: L
authors.lastname: Colliandre
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Mérour
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008872:Microwaves; D008958:Models, Molecular; D008968:Molecular Conformation; D010165:Palladium / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D010165:Palladium; D011494:Protein Kinases