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

• Published in: Bioorganic & medicinal chemistry 2016-05, Vol.24 (10), p.2330-2341
• Main Authors: Lewandowska, Marta, Ruszkowski, Piotr, Chojnacka, Kinga, Kleczewska, Natalia, Hoffmann, Marcin, Kacprzak, Karol, Celewicz, Lech
• Format: Article
• Language: English
• Subjects: 5-Fluoro-2′-deoxyuridine phosphoramidates; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxic activity; Deoxyuridine - analogs & derivatives; Deoxyuridine - chemical synthesis; Deoxyuridine - chemistry; Deoxyuridine - pharmacology; Human cancer cell lines: HeLa, KB, MCF-7, HepG2, 143B; Humans; Neoplasms - drug therapy; Normal human cell line: HDF; Phosphoric Acids - chemical synthesis; Phosphoric Acids - chemistry; Phosphoric Acids - pharmacology; Phosphorylation
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.04.003

[Display omitted] 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.