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.

Preparation of Pyrimidine Alkenyl Acyclic Nucleoside Phosphonoamidates

“…In recent years, the ProTide approach, pioneered by Chris McGuigan's group, has displayed a great deal of success in the development of nucleoside‐based antivirals and anticancer drugs (Pertusati, McGuigan, & Serpi, ; Serpi et al., ). Sofosbuvir (Nakamura et al., ) and TAF (Abdul Basit, Dawood, Ryan, & Gish, ; Ray, Fordyce, & Hitchcock, ), on the market for viral infections, and Acelerin (Slusarczyk et al., ) and NUC 3373 (McGuigan et al., ), in clinical trials (Phase III and Phase I) for patients with advanced solid tumors, are the undeniable proof of how powerful this technology is.…”

Fluorinated Nucleosides as an Important Class of Anticancer and Antiviral Agents

“…Phosphoramidates consist of a 5'-masked monophosphate moiety (built using: an amino acid ester and aryloxy group) introduced into the nucleoside template at the 5'-position, which, after cellular nucleosidetransporter-independent uptake and subsequent intracellular metabolism, deliver the 5'-monophosphate form [29]. …”

5-Fluorouracil derivatives: a patent review (2012 – 2014)

“…In recent years, an interesting strategy to overcome these drawbacks has been the development of phosphoramidate prodrugs of 5-FdUrd (e.g., CPF-373) by the pronucleotide approach method. This prodrug technology consists in the delivery of nucleotide monophosphate into the cells, circumventing the phosphorylation step of those nucleosides [87]. Compounds synthesized act inhibiting TS independently of TK status and can deliver nucleoside monophosphates into the intact tumor cell.…”

“…As examples, the administration of FOLFIRI and bevacizumab for patients with unresectable metastatic cancer [87] or oxaliplatin-based chemotherapy plus bevacizumab are active combinations as first-line treatment of advanced colorectal cancer [89]Several clinical trials are being conducted based on the combination of 5-FU with several drugs such as the combination of cetuximab, gemcitabine and radiotherapy. In pancreatic cancer, where patients are diagnosed at advanced stage of the disease and the only treatment with long-term survival is surgery, modest improvements on survival have recently been reported with FOLFORINOX (FOLFIRI + oxaliplatin) [90] or albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine [91].…”