title: Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors.
abstract: We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 μM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM.
authors.affiliation: Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France; Equipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
authors.forename: Oussama
authors.initials: O
authors.lastname: Dehbi
authors.affiliation: Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France; Equipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Tikad
authors.affiliation: Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bourg
authors.affiliation: Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonnet
authors.affiliation: C.N.R.S., Protein Phosphorylation & Human Disease, USR3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.affiliation: C.N.R.S., Protein Phosphorylation & Human Disease, USR3151, Station Biologique, B.P. 74, 29682 Roscoff Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Equipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
authors.forename: Mina
authors.initials: M
authors.lastname: Aadil
authors.affiliation: Equipe de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akssira
authors.affiliation: Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France. Electronic address: gerald.guillaumet@univ-orleans.fr.
authors.forename: Gérald
authors.initials: G
authors.lastname: Guillaumet
authors.affiliation: Institut de Chimie Organique et Analytique, CNRS UMR 7311, B.P. 6759, 45067 Orléans Cedex 2, France. Electronic address: sylvain.routier@univ-orleans.fr.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
mesh_terms: D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D000097603:Dyrk Kinases; C030986:pyrimidine
keywords: CDK5; DYRK1A; Molecular modelling; Pyridopyrimidine; SAR; Synthesis