Synthesis of 3′-azido-2′,3′-dideoxy-5-fluorouridine phosphoramidates and evaluation of their anticancer activity

• Published in: European journal of medicinal chemistry 2013-09, Vol.67, p.188-195
• Main Authors: Lewandowska, Marta, Ruszkowski, Piotr, Baraniak, Dagmara, Czarnecka, Anna, Kleczewska, Natalia, Celewicz, Lech
• Format: Article
• Language: English
• Subjects: 3’-Azido-2′,3′-dideoxy-5-fluorouridine phosphoramidates; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cytotoxic activity; Dose-Response Relationship, Drug; Floxuridine - analogs & derivatives; Floxuridine - chemical synthesis; Floxuridine - chemistry; Floxuridine - pharmacology; HeLa Cells; Human cancer cell lines: HeLa, KB and MCF-7; Humans; KB Cells; MCF-7 Cells; Molecular Structure; Phosphorylation; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.06.047

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-azido-2′,3′-dideoxy-5-fluorouridine (12–21) were synthesized by means of phosphorylation of 3′-azido-2′,3′-dideoxy-5-fluorouridine (4) with 4-chlorophenyl phosphoroditriazolide (10) followed by a reaction with the appropriate amine. The synthesized phosphoramidates (12–21) were evaluated for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7) using the sulforhodamine B (SRB) assay. The highest activity in all the investigated cancer cells was displayed by phosphoramidate 13 with the N-ethyl substituent and its activity was much higher than that of the parent nucleoside. Also phosphoramidate 17 with the N-propargyl substituent exhibited good activity in all the used cell lines. [Display omitted] A series of 4-chlorophenyloxy N-alkyl phosphoramidates of 3′-azido-2′,3′-dideoxy-5-fluorouridine were synthesized and evaluated for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB) and breast (MCF-7). •Phosphoramidates of 3′-azido-2′,3′-dideoxy-5-fluorouridine were synthesized.•Obtained phosphoramidates were evaluated for their cytotoxic activity.•The highest activity was displayed by phosphoramidate with the N-ethyl substituent.•Phosphoramidate with N-propargyl substituent exhibited also fairly high activity.