Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides
- Bioorg Med Chem. 2018 Feb 1;26(3):551-565. doi: 10.1016/j.bmc.2017.11.037.
- 1. School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: [email protected].
- 2. School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, King Edward VII Avenue, Cardiff CF10 3NB, UK.
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.