Dual pro-drugs of 2′-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus

Phosphoramidate Prodrugs of (−)-β-D-(2R,4R)-dioxolane-thymine (DOT) as Potent Anti-HIV Agents

“…Therefore, naphthyl phosphoramidate 11 and its L-DOT analogue 11B, were synthesized, and their anti-HIV activity and cytotoxicity were investigated. Compound 11 displayed potent anti-HIV activity with an EC 50 of 0.46 mM; but compound 11 exhibited modest cytotoxicity with a CC 50 of 57.4 mM similar to results obtained with naphthyl substituted nucleosides studied for HCV [16,20]. However, its L-DOT analogue 11B, with an identical ProTide motif, lacked toxicity.…”

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…In some cases, they both provide similar yields like in the case of 2′- C -methyl-2-amino-6-substituted-purine ribonucleoside analogs 183 and 5-FdU (Scheme 105). 184 …”

Synthesis of Phosphoramidate Prodrugs: ProTide Approach

“…In the 1990s (McGuigan et al, ), during a study aimed to discover potential prodrugs for HIV, several aryloxy 5′‐phosphoramidate nucleoside prodrugs (ProTide) were shown to may be able to bypass the first problematic kinase‐promoted phosphorylation step and eventually lead to the active triphosphorylated species. After that the ProTide technology was successfully and extensively applied to a high number of nucleoside phosphates endowed with antiviral and anticancer activity (Derudas et al, , ,b; Mehellou et al, , ; McGuigan et al, ,b, ; Meneghesso et al, ). The ProTide technology was also investigated for phosphonate prodrugs (Ballatore et al, ) and recently applied for the delivery of sugar monophospate as potential anti‐osteoarthritic drugs (McGuigan et al, ; Serpi et al, ).…”

“…This unit describes two different synthetic strategies for the preparation of phosphoramidate prodrugs using, respectively, 6‐ O ‐methyl‐2′−β‐ C ‐methylguanosine and 2′−β ‐ D ‐arabinouridine (AraU) as nucleosidic models. In the first, tert ‐butyl magnesium chloride ( t BuMgCl) is used as a base for the coupling reaction between the 6‐ O ‐methyl‐2′−β‐ C ‐methylguanosine nucleoside (or similar nucleoside having only the 5′‐OH as a reactive site) and the phosphorochloridate bearing the desired promoieties (McGuigan et al, ). In the second approach, N ‐methyl imidazole (NMI) is used in place of tert ‐butyl magnesium chloride for the same reaction when AraU (or similar nucleoside, containing two or more reactive hydroxyl groups) is used (Mehellou et al, ).…”