Download MendeleyStructure-activity relationships of orotidine-5'-monophosphate decarboxylase inhibitors as anticancer agents.
Bello, A.M., Konforte, D., Poduch, E., Furlonger, C., Wei, L., Liu, Y., Lewis, M., Pai, E.F., Paige, C.J., Kotra, L.P.(2009) J Med Chem 52: 1648-1658
- PubMed: 19260677
- DOI: https://doi.org/10.1021/jm801224t
- Primary Citation of Related Structures:
3G3D, 3G3M, 3S9Y - PubMed 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.
- 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.
Organizational Affiliation:
