pyrazofurin and 5-fluorouridine

A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.

Topics: Antineoplastic Agents; Antiviral Agents; Binding Sites; Cell Line, Tumor; Cell Survival; Chikungunya virus; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Nerve Tissue Proteins; Phosphoramides; Prodrugs; Protein Structure, Tertiary; Structure-Activity Relationship; Uridine; Virus Internalization

Topics: Amides; Animals; Antimetabolites, Antineoplastic; Drug Interactions; Drug Therapy, Combination; Female; Fluorouracil; Hematopoietic Stem Cells; Male; Mice; Neoplasms, Experimental; Pyrazoles; Ribonucleosides; Ribose; Uridine