McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X, Bourdin, Claire, Derudas, Marco, Hamon, Nadege, Hinsinger, Karen, Kandil, Sahar ORCID: https://orcid.org/0000-0003-1806-9623, Madela, Karolina, Meneghesso, Silvia, Pertusati, Fabrizio ORCID: https://orcid.org/0000-0003-4532-9101, Serpi, Michaela ORCID: https://orcid.org/0000-0002-6162-7910, Slusarczyk, Magdalena ORCID: https://orcid.org/0000-0002-4707-7190, Chamberlain, Stanley, Kolykhalov, Alexander, Vernachio, John, Vanpouille, Christophe, Introini, Andrea, Margolis, Leonid and Balzarini, Jan 2013. Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides. European Journal of Medicinal Chemistry 70 , pp. 326-340. 10.1016/j.ejmech.2013.09.047 |
Preview |
PDF
- Accepted Post-Print Version
Download (1MB) | Preview |
Abstract
We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-Alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by 31P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields.
Item Type: | Article |
---|---|
Date Type: | Publication |
Status: | Published |
Schools: | Pharmacy Systems Immunity Research Institute (SIURI) |
Subjects: | R Medicine > RM Therapeutics. Pharmacology |
Uncontrolled Keywords: | Nucleoside analogs; Antiviral; Anticancer; Phosphorodiamidates; Prodrugs |
Publisher: | Elsevier |
ISSN: | 0223-5234 |
Date of First Compliant Deposit: | 30 March 2016 |
Last Modified: | 07 Nov 2024 04:15 |
URI: | https://orca.cardiff.ac.uk/id/eprint/53043 |
Citation Data
Cited 21 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
Edit Item |