SATE Pronucleotide Approaches: An Overview

Abstract

This review depicts in vitro and in vivo results obtained with nucleotide prodrugs (pronucleotides) bearing S-acyl-2-thioethyl (SATE) groups as esterase-labile phosphate protections. New developments are illustrated by the design of mononucleoside mixed phosphoester derivatives leading to the selective intracellular delivery of the corresponding 5'-mononucleotide through two different enzyme-mediated activation steps.

Decomposition of 3′‐azido‐2′,3′‐dideoxythymidine 5′‐monophosphate (AZTMP) prodrugs in biological media studied by on‐line solid‐phase extraction coupled to liquid chromatography mass spectrometry

“…In the past decades, several strategies have been developed to improve the therapeutic potential of nucleoside analogs using pronucleotides (Cahard et al, 2004;Drontle and Wagner, 2004;Jessen et al, 2008;Meier et al, 2004;Parang et al, 2000;Peyrottes et al, 2004;Schultz, 2003). These investigations have been associated with the development of different approaches in order to demonstrate the selectivity of processes involved in the intracellular delivery of 5′-mononucleotide from its phosphorylated precursor.…”

“…We previously demonstrated in other pronucleotide series of AZT that a fast intracellular release of the 5′-mononucleotide would be better in order to observe a potent anti-HIV effect in CEM-TK − cells (Peyrottes et al, 2004). Thus, an increase in the enzymatic stability in CEM cell extracts of a pronucleotide is usually correlated to a decrease in its antiviral activity.…”

“…In order to circumvent this limitation, the use of 5′-mononucleotides could not be envisaged due to their polar nature under physiological conditions (limiting their ability to cross cell membranes) and their rapid dephosphorylation in extracellular fluids and on cell surfaces (Ho, 1971;Jessen et al, 2008;LePage et al, 1975;Schrecker and Goldin, 1968). Consequently, several approaches have been developed to improve the therapeutic potential of nucleoside analogs using mononucleotide prodrugs (pronucleotides) (Cahard et al, 2004;Drontle and Wagner, 2004;Meier et al, 2004;Peyrottes et al, 2004). The difficulty of a pronucleotide approach lies in the fact that transformations involved in the 5′-mononucleotide delivery from its corresponding prodrug selectively occur inside the cells.…”

Molecular tools for cell and systems biology

“…Due to the negative potential of the plasma membrane maintained by most cells (from −50 to −70 mV), negatively charged compounds are literately repelled from crossing membranes, while partially positively charged molecules are more likely to penetrate. Medicinal chemists therefore developed bioactivatable protecting groups such as alkyoxymethyl esters and S-alkylthioethyl esters, just to name a couple (Friis and Bundgaard, 1996;Peyrottes et al, 2004;Schultz, 2003). The resulting protected molecules are usually referred to as prodrugs or "Trojan horse" compounds.…”

“…10). Most work so far has been done on ion chelators (Grynkiewicz et al, 1985;Tsien, 1981), nucleotides (Friis and Bundgaard, 1996;Peyrottes et al, 2004;Schultz, 2003;Schultz et al, 1994Schultz et al, , 1993, inositol phosphates (Li et al, 1998;Rudolf et al, 2003;Vajanaphanich et al, 1994), phosphoinositides (Dinkel et al, 2001;Jiang et al, 1998), and other lipid derivatives . In addition, some small molecule sensor molecules (Wichmann et al, 2006;Zlokarnik et al, 1998) but also some commercial drugs rely on this technique (Krapcho et al, 1988;Starret et al, 1994;von Daehne et al, 1970).…”