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

  • Bioorg Med Chem. 2016 May 15;24(10):2330-41. doi: 10.1016/j.bmc.2016.04.003.
Marta Lewandowska  1 ,  Piotr Ruszkowski  2 ,  Kinga Chojnacka  1 ,  Natalia Kleczewska  1 ,  Marcin Hoffmann  1 ,  Karol Kacprzak  1 ,  Lech Celewicz  3
Affiliations
  • 1. Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland.
  • 2. Department of Pharmacology, Poznań University of Medical Sciences, Rokietnicka St 5 a, 60-806 Poznań, Poland.
  • 3. Faculty of Chemistry, Adam Mickiewicz University, Umultowska St 89 b, 61-614 Poznań, Poland. Electronic address: [email protected].
PMID: 27073055 DOI: 10.1016/j.bmc.2016.04.003
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.

Keywords
5-Fluoro-2′-deoxyuridine phosphoramidates; Cytotoxic activity; Human cancer cell lines: HeLa, KB, MCF-7, HepG2, 143B; Normal human cell line: HDF; Phosphorylation.