Mononucleotide Prodrug Synthetic Strategies

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…Reviews on nucleoside phosph(on)ate prodrugs generally focus on their enhanced biological activities, potential therapeutic interest, and their physicochemical properties, 6 , 7 but almost completely neglect their sometimes challenging synthetic preparation. 8 Herein, we review the most important mono-, di-, and triphosphate and phosphonate prodrug approaches applied to nucleoside analogs (Figure 3 ) from a chemical point of view, detailing the strengths and limitations of each approach. We will focus on the various synthetic pathways discussing (1) the chemical variation of the biolabile phosph(on)ate masking groups; (2) the reliability of using P(III) and/or P(V) chemistry for both phosphate and phosphonate prodrug synthesis; (3) the influence of the masking group(s) introduction conditions (solvent, temperature, stoichiometry) on the overall outcome for each method; (4) the various protection/deprotection strategies used to impart improved yield and regioselectivity relative to the nature of the nucleobase and the sugar; and (5) the influence of reaction conditions or protective groups on the stereoselectivity ( R p / S p ) observed at the phosphorus center as well as the methods employed to separate both R p and S p isomers along with the asymmetric strategies for the synthesis of predominantly single diastereoisomers at the phosphorus center.…”

Design, Synthesis and Antiviral Evaluation of 2′- C -Methyl Branched Guanosine Pronucleotides: The Discovery of IDX184, a Potent Liver-Targeted HCV Polymerase Inhibitor

“…Synthesis & anti-HCV evaluation of three 2′-C-methylguanosine-5′-[2-[(3-hydroxy-2,2dimethyl-1-oxopropyl)thio]ethyl N-(alkyl) phosphoramidate derivatives]: IDX184, compounds 6 & 7 In order to achieve intracellular delivery of nucleoside analog monophosphates, numerous prodrug strategies (pronucleotide approaches) have been explored [34][35][36][37][38][39][40][41], where at least one ionisable P(=O)(OH) 2 group of the nucleoside monophosphate has been esterified or converted into a phosphoramidate function. Among the main pronucleotide approaches hitherto reported, we can cite those using a pivaloyloxymethyl (POM) [42], an isopropyloxycarbonyloxymethy (POC) [43], a 2-(2-hydroxyethyldisulfanyl)ethyl (DTE) [44][45][46][47] or an (S-acyl-2-thioethyl) (SATE) [44][45][46]48] function as biolabile promoieties, as well as the CycloSal [49][50][51][52], the HepDirect [53,54], the ProTide [30,[55][56][57] and the phosphoramidate monoester approaches [58][59][60].…”

An original pronucleotide strategy for the simultaneous delivery of two bioactive drugs

“…1), a phosphoramidate pronucleotide with broad-spectrum activities against RNA viruses , has been proposed for the treatment of coronavirus disease-2019 5 . First disclosed by McGuigan et al 6 , such kind of pronucleotides (i.e. mononucleoside aryl phosphoramidate diesters) were developed to address not only bioavailability issues but also poor in vivo conversion of the parent nucleoside into its corresponding 5'-monophosphorylated form (5'-mononucleotide).…”

“…(m, 9H, CH3OPh, Ph), 6.88 (s, 1H, NH),6.69 (d, 4H, J = 8.9 Hz, CH3OPh), 5.96 (dd, 1H, J = 7.6 Hz, J = 6.2 Hz, H-1'), 5.89 (d, 1H, J = 9.4 Hz, OH), 4.24 (m, 1H, H-4'), 3.89 (d, 1H, J = 12.6 Hz, H-5'), 3.68 (s, 6H, CH3OPh), 3.49 (m, 1H, H-5''), 2.69 (m, 1H, H-2'), 2.33 (m, 1H, H-3'), 2.23 (m, 2H, H-2''), 2.10 (m, 1H, H-3''); NMR 13 C (CDCl3, 100 MHz)  158.3 (1s, CH3OPh ipso), 154.5 (1s, C-6), 151.7 (1s, C-2), 147.7 (1s, C-4), 145.2 (1s, Ph ipso), 139.2 (1s, C-8), 137.3-137.2-130.0 (3s, CH3OPh), 128.3-127.9-126.8 (3s, Ph), 122.3 (1s, C-5), 113.1 (1s, CH3OPh), 88.3 (1s, C-1'), 81.6 (1s, C-4'), 70.7 (1s, C[(CH3OPh)2Ph]), 65.1 (1s, C-5'), 55.2 (1s, CH3OPh), 32.2 (1s, C-2'), 26.2 (1s, C-3'); MS FAB>0 (GT) m/z 538 (M+H) + . FAB<0 (GT) m/z 1073 (2M-H) -, 536 (M-H) -, 436 (B) -; UV (ethanol 95) λmax 276 nm ( 22 300), λmin 249 nm ( 10 800); HPLC tR 28.3 min; Anal.…”