title: Synthesis of purin-2-yl and purin-6-yl-aminoglucitols as C-nucleosidic ATP mimics and biological evaluation as FGFR3 inhibitors.
abstract: Two new series of C-nucleosidic ATP mimics have been synthesized using an efficient and versatile synthetic pathway. These compounds were designed as FGFR3 inhibitors using purine as a central scaffold. The two substituents, a polyhydroxylated ribose mimic and a lipophilic moiety, were linked either in position 2 or 6 of the purine ring in order to explore any possible binding mode. All the compounds were able to inhibit FGFR3 kinase activity at a concentration of 50 μM. Unexpectedly, the best inhibitor was found to be one of the synthetic intermediates 13 bearing an iodine atom in position 2. Docking studies have confirmed its location in the ATP binding site and revealed halogen bonding among key interactions.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, UMR 8601, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Lotfi
authors.initials: L
authors.lastname: Tak-Tak
authors.forename: Florent
authors.initials: F
authors.lastname: Barbault
authors.forename: François
authors.initials: F
authors.lastname: Maurel
authors.forename: Patricia
authors.initials: P
authors.lastname: Busca
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Merrer
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012266:Ribose / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013012:Sorbitol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D013012:Sorbitol; D012266:Ribose; D000255:Adenosine Triphosphate; D051498:Receptor, Fibroblast Growth Factor, Type 3