Structure-activity relationships of orotidine-5'-monophosphate decarboxylase inhibitors as anticancer agents.

Research paper by Angelica M AM Bello, Danijela D Konforte, Ewa E Poduch, Caren C Furlonger, Lianhu L Wei, Yan Y Liu, Melissa M Lewis, Emil F EF Pai, Christopher J CJ Paige, Lakshmi P LP Kotra

Indexed on: 06 Mar '09Published on: 06 Mar '09Published in: Journal of Medicinal Chemistry


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.