title: Structure-activity relationships of orotidine-5'-monophosphate decarboxylase inhibitors as anticancer agents.
abstract: A series of 6-substituted and 5-fluoro-6-substituted uridine derivatives were synthesized and evaluated for their potential as anticancer agents. The designed molecules were synthesized from either fully protected uridine or the corresponding 5-fluorouridine derivatives. The mononucleotide derivatives were used for enzyme inhibition investigations against ODCase. Anticancer activities of all the synthesized derivatives were evaluated using the nucleoside forms of the inhibitors. 5-Fluoro-UMP was a very weak inhibitor of ODCase. 6-Azido-5-fluoro and 5-fluoro-6-iodo derivatives are covalent inhibitors of ODCase, and the active site Lys145 residue covalently binds to the ligand after the elimination of the 6-substitution. Among the synthesized nucleoside derivatives, 6-azido-5-fluoro, 6-amino-5-fluoro, and 6-carbaldehyde-5-fluoro derivatives showed potent anticancer activities in cell-based assays against various leukemia cell lines. On the basis of the overall profile, 6-azido-5-fluoro and 6-amino-5-fluoro uridine derivatives exhibited potential for further investigations.
authors.affiliation: Center for Molecular Design and Preformulations and Division of Cellular and Molecular Biology, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Bello
authors.forename: Danijela
authors.initials: D
authors.lastname: Konforte
authors.forename: Ewa
authors.initials: E
authors.lastname: Poduch
authors.forename: Caren
authors.initials: C
authors.lastname: Furlonger
authors.forename: Lianhu
authors.initials: L
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Melissa
authors.initials: M
authors.lastname: Lewis
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009964:Orotidine-5'-Phosphate Decarboxylase