Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

• Published in: European journal of medicinal chemistry Vol. 70; pp. 326 - 340
• Main Authors: McGuigan, Christopher, Bourdin, Claire, Derudas, Marco, Hamon, Nadège, Hinsinger, Karen, Kandil, Sahar, Madela, Karolina, Meneghesso, Silvia, Pertusati, Fabrizio, Serpi, Michaela, Slusarczyk, Magdalena, Chamberlain, Stanley, Kolykhalov, Alexander, Vernachio, John, Vanpouille, Christophe, Introini, Andrea, Margolis, Leonid, Balzarini, Jan
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2013; Elsevier
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Sciences; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; HeLa Cells; HIV-1 - drug effects; HIV-2 - drug effects; Humans; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Nucleoside analogs; Nucleosides - chemistry; Pharmacology & Pharmacy; Phosphorodiamidates; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Science & Technology; Structure-Activity Relationship; Phosphorodiamidates; Antiviral; Prodrugs; Anticancer; Nucleoside analogs; ACYCLOVIR; VIRUS; PHOSPHORYLATION; DRUGS; TRIESTERS; PHOSPHORAMIDATE PROTIDE TECHNOLOGY; DISCOVERY
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2013.09.047

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. [Display omitted] •Application of diamidate approach to nucleoside analogs as potential antiviral and anticancer agents.•A markedly improved antiviral activity was observed in some cases, whilst the parent nucleosides were inactive.•Inhibitory effect on the proliferation of tumor cell lines was also demonstrated.