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Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism

Mehellou, Youcef, Valente, Rocco, Mottram, Huw James, Walsby, Elisabeth Jane, Mills, Kenneth Ian, Balzarini, Jan and McGuigan, Christopher 2010. Phosphoramidates of 2′-β-d-arabinouridine (AraU) as phosphate prodrugs; design, synthesis, in vitro activity and metabolism. Bioorganic & Medicinal Chemistry 18 (7) , pp. 2439-2446. 10.1016/j.bmc.2010.02.059

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2′-β-d-Arabinouridine (AraU), the uridine analogue of the anticancer agent AraC, was synthesized and evaluated for antiviral activity and cytotoxicity. In addition, a series of AraU monophosphate prodrugs in the form of triester phosphoramidates (ProTides) were also synthesized and tested against a range of viruses, leukaemia and solid tumour cell lines. Unfortunately, neither the parent compound (AraU) nor any of its ProTides showed antiviral activity, nor potent inhibitory activity against any of the cancer cell lines. Therefore, the metabolism of AraU phosphoramidates to release AraU monophosphate was investigated. The results showed carboxypeptidase Y, hog liver esterase and crude CEM tumor cell extracts to hydrolyse the ester motif of phosphoramidates with subsequent loss of the aryl group, while molecular modelling studies suggested that the AraU l-alanine aminoacyl phosphate derivative might not be a good substrate for the phosphoramidase enzyme Hint-1. These findings are in agreement with the observed disappearance of intact prodrug and concomitant appearance of the corresponding phosphoramidate intermediate derivative in CEM cell extracts without measurable formation of araU monophosphate. These findings may explain the poor antiviral/cytostatic potential of the prodrugs.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Antiviral; Nucleosides; Nucleotides; Prodrugs; Protides; Anticancer
Publisher: Elsevier
ISSN: 0968-0896
Last Modified: 31 Jan 2020 05:16

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