Synthesis and anticancer activity of some 5-fluoro-2′-deoxyuridine phosphoramidates

Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-O-(t-butoxycarbonyl)-5-fluoro-2′-deoxyuridine (3′-BOC-FdU) (9a–9j) and 5-fluoro-2′-deoxyuridine (FdU) (10a–10j) were synthesized by means of phosphorylation of 3′-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a–9j were converted to the corresponding 10a–10j by removal of the 3′-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a–9j and 10a–10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a–10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.

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