title: Novel interactions of fluorinated nucleotide derivatives targeting orotidine 5'-monophosphate decarboxylase.
abstract: Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists because of their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2'-deoxy-2'-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine 5'-monophosphate decarboxylase (ODCase or OMPDCase). These compounds were synthesized from the key intermediate, fully protected 2'-deoxy-2'-fluorouridine. Among the synthesized compounds, 2'-deoxy-2'-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 ± 0.02 M(-1) s(-1). Interestingly, the 6-cyano-2'-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2'-fluoro moiety influences the chemistry at the C6 position of the nucleotides and thus interactions in the active site of ODCase. Molecular interactions of the 2'-fluorinated nucleotides are compared to those with the 3'-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations.
authors.affiliation: Center for Molecular Design and Preformulations and Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lewis
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Meza-Avina
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.forename: Ian E
authors.initials: IE
authors.lastname: Crandall
authors.forename: Angelica Mara
authors.initials: AM
authors.lastname: Bello
authors.forename: Ewa
authors.initials: E
authors.lastname: Poduch
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D009711:Nucleotides; D005461:Fluorine; D009964:Orotidine-5'-Phosphate Decarboxylase