title: Synthesis and anticancer activity of some 5-fluoro-2'-deoxyuridine phosphoramidates.
abstract: 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.
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Lewandowska
authors.affiliation: Department of Pharmacology, Poznań University of Medical Sciences, Rokietnicka St 5 a, 60-806 Poznań, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruszkowski
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Chojnacka
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kleczewska
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Kacprzak
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland. Electronic address: celewicz@amu.edu.pl.
authors.forename: Lech
authors.initials: L
authors.lastname: Celewicz
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C576827:5-fluoro-2'-deoxyuridine; D000577:Amides; D000970:Antineoplastic Agents; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D003857:Deoxyuridine
keywords: 5-Fluoro-2′-deoxyuridine phosphoramidates; Cytotoxic activity; Human cancer cell lines: HeLa, KB, MCF-7, HepG2, 143B; Normal human cell line: HDF; Phosphorylation