Synthesis and Antiviral Evaluation of SATE-Foscarnet Prodrugs and New Foscarnet—AZT Conjugates

Abstract

The synthesis of a range of di- and triester derivatives of phosphonoformate (PFA; foscarnet) as potential lipophilic, membrane-soluble prodrugs is described. In addition to normal alkyl esters in the carboxylate and phosphonate residues of PFA, the bioreversible S-(pivaloyl)thioethyl (t-butyl-SATE) group was introduced in an attempt to deliver PFA after bioactivation inside the cells. Furthermore, PFA-AZT conjugates were prepared in order to develop combinational drugs. The key synthetic step was in all cases the formation of the P-C bond to build up the different PFA esters. In contrast to the diester derivatives, the triesters of PFA showed high hydrolytic instability during chromatographic purification. The compounds were evaluated in vitro for their ability to inhibit viruses in several tissue culture systems. All PFA alkyl di- and triesters proved poorly active or inactive against human immunodeficiency virus (HIV) and inactive against hepatitis B virus. In contrast, the PFA-AZT conjugates exhibited significant anti-HIV activity. However, this activity was nearly completely lost in thymidine kinase-deficient cells, suggesting a fast unselective chemical hydrolysis of the conjugates to yield the nucleoside analogue AZT in the cell culture medium. Furthermore, no synergistic effect of PFA and AZT was observed.

Polymeric nanogel formulations of nucleoside analogs

“…Most nucleoside prodrugs include advanced oral forms or hydrophobic derivatives with superior bio-availability [14][15][16]. However, successful applications of this approach using NTP only include covalent phospholipid conjugates of anti-HIV drug, 3′-azidothymidine (AZT) demonstrating a higher bioavailability and lower toxicity than AZT [17].…”

Neoglycolipid Conjugates of Foscarnet with Enhanced Antiviral Activity in Cells Infected with Human Cytomegalovirus and Herpes Simplex Virus Type 1

“…In order to prepare the 6-Ocarboxyphosphonyl derivatives, the alkyl glycopyranosides were first 6-O-tritylated, then benzoylated to give after detritylation the alkyl 2,3,4-tri-O-benzoylglycopyranoside (4a-g). In order to introduce the carboxyphosphonyl substituent, a method for the synthesis of monoalkyl phosphonates (Sasse, 1963), which has previously been used for the synthesis of foscarnet monoalkyl esters (Meier et al, 1998), was employed. Reaction of the partially protected glycoside (4a-g) with 1.6 equivalents of ethoxycarbonylphosphonic dichloride gave in good yield after aqueous work-up the 6-O-ethoxycarbonylphosphonyl derivative (5a-g), which was deprotected by hydrolysis in dilute aqueous NaOH to afford the final product (6a-g).…”

“…Attempts have been made to improve oral absorption by formation of bioreversible prodrugs designed to release foscarnet following uptake from the gastrointestinal tract (Briggs et al, 1996(Briggs et al, , 1997Meier et al, 1998), but this approach has not been particularly successful. However, lipid prodrugs of foscarnet such as 1-O-octadecyl-sn-glycero-3-phosphonoformate show enhanced antiviral activity as a result of their improved cell penetration followed by intracellular release of foscarnet (Hostetler et al, 1996).…”

“…In previous studies, alkyl, aryl, acyloxymethyl, 4-acyloxybenzyl and S-acylthioethyl mono-, di-and triesters of foscarnet have been prepared as potential bioreversible prodrugs (Norén et al, 1983;Iyer et al, 1989Iyer et al, , 1994Briggs et al, 1996Briggs et al, , 1997Meier et al, 1998). It has previously been shown that triesters of foscarnet are not suitable as prodrugs owing to their instability towards chemical hydrolysis at physiological pH and their propensity to undergo primarily P-C bond scission (Krol et al, 1991;Mitchell et al, 1991Mitchell et al, , 1992Krol & Thatcher, 1993).…”

Synthesis and in vitro activities of a new antiviral duplex drug linking Zidovudine (AZT) and Foscarnet (PFA) via an octadecylglycerol residue

“…15 The first synthesized antiviral molecules linking AZT and PFA were conjugates, in which the carboxyl or phosphonyl group of PFA ester derivatives was directly covalently linked to the 5 0 -hydroxyl group of AZT or other inhibitory dideoxynucleoside analogues. [16][17][18][19] The evaluated antiviral activity of these types of conjugates neither achieved substantial gains in terms of antiviral activity nor in therapeutic selectivity. The more recently developed lipophilic AZT-PFA conjugates, in which the formic terminal of PFA was esterified with a long chain alkyl alcohols, whereas the phosphono terminal of PFA was coupled to the 5 0 -hydroxyl group of AZT, have the potential to act either as PFA prodrugs, AZT-prodrugs or both.…”