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Synthesis and Anticancer Activity of Some 5-fluoro-2'-deoxyuridine Phosphoramidates

Synthesis and Anticancer Activity of Some 5-fluoro-2'-deoxyuridine Phosphoramidates

Marta Lewandowska, Piotr Ruszkowski, Kinga Chojnacka, Natalia Kleczewska, Marcin Hoffmann, Karol Kacprzak, Lech Celewicz

Bioorg Med Chem. 2016 May 15;24(10):2330-41.

PMID: 27073055

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP50919-B	5-Fluoro-2′-deoxyuridine		50-91-9	Price

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