title: Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides.
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 (31)P 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: mcguigan@cardiff.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Claire
authors.initials: C
authors.lastname: Bourdin
authors.forename: Marco
authors.initials: M
authors.lastname: Derudas
authors.forename: Nadège
authors.initials: N
authors.lastname: Hamon
authors.forename: Karen
authors.initials: K
authors.lastname: Hinsinger
authors.forename: Sahar
authors.initials: S
authors.lastname: Kandil
authors.forename: Karolina
authors.initials: K
authors.lastname: Madela
authors.forename: Silvia
authors.initials: S
authors.lastname: Meneghesso
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pertusati
authors.forename: Michaela
authors.initials: M
authors.lastname: Serpi
authors.forename: Magdalena
authors.initials: M
authors.lastname: Slusarczyk
authors.forename: Stanley
authors.initials: S
authors.lastname: Chamberlain
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolykhalov
authors.forename: John
authors.initials: J
authors.lastname: Vernachio
authors.forename: Christophe
authors.initials: C
authors.lastname: Vanpouille
authors.forename: Andrea
authors.initials: A
authors.lastname: Introini
authors.forename: Leonid
authors.initials: L
authors.lastname: Margolis
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D009705:Nucleosides; D011355:Prodrugs
keywords: Anticancer; Antiviral; Nucleoside analogs; Phosphorodiamidates; Prodrugs