title: Synthesis of phosphoramidate prodrugs: ProTide approach.
abstract: The ProTide (pronucleotide) approach is a prodrug strategy elaborated to deliver nucleoside monophosphate into the cell, circumventing the first and inefficient rate-limiting phosphorylation step of nucleosides and improving the cellular penetration of nucleotides. The ProTide of a nucleoside phosphate is a phosphoramidate prodrug consisting of an amino acid ester promoiety linked via P-N bond to a nucleoside aryl phosphate. Such prodrugs have increased lipophilicity and thus are capable of altering cell and tissue distribution. The ProTide technology was successfully and extensively applied to a wide variety of nucleoside phosphates, endowed with antiviral and anticancer activity. This unit describes two different synthetic strategies allowing the preparation of phosphoramidates of 6-O-methyl-2'-β-C-methylguanosine as model compounds for nucleosides having only the 5'-OH as reactive hydroxyl group, and phosphoramidates of 2'-β-D-arabinouridine (AraU) as model compounds for nucleosides containing two or more reactive hydroxyl groups.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michaela
authors.initials: M
authors.lastname: Serpi
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Karolina
authors.initials: K
authors.lastname: Madela
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pertusati
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Slusarczyk
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004952:Esters / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism*; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004952:Esters; D009705:Nucleosides; D009711:Nucleotides; D011355:Prodrugs; D006151:Guanosine; C046175:6'-O-methylguanosine