cycloSal-PMEA and cycloAmb-PMEA:  Potentially New Phosphonate Prodrugs Based on the cycloSal-Pronucleotide Approach

Abstract

Two new classes of lipophilic prodrugs of the antiviral active phosphonate 9-[2-phosphonomethoxyethyl]adenine (PMEA 1) have been prepared and were studied with regard to their hydrolysis properties and biological activity. A first series of compounds was prepared on the basis of the cycloSal nucleotide approach. Because of the surprisingly low hydrolysis stability of these cycloSal-PMEA derivatives, more stable derivatives have to be developed. Instead of using salicyl alcohol, in cycloAmb-PMEA derivatives 2-aminobenzyl alcohols were attached to PMEA 1. The latter compounds showed a considerably higher stability compared to the cycloSal counterparts. Stability studies revealed that all lipophilic prodrugs delivered PMEA selectively by chemical means. All compounds proved to be noninhibiting to acetyl- and butyrylcholinesterase, and some of the phosphonate diesters were found to be more active against HIV compared to the parent PMEA.

NewCycloAMB-Nucleoside Phosphonate Prodrugs

“…According to these results we found antiviral activities of the new prodrugs that do not reach the activity of parent PMEA (Table 1). Compared to the published cycloAmb-PMEA prodrugs [5] 4-Me-and 6-cycloAmb-PMEA show a slight improvement of antiviral activity. Surprisingly, the cytotoxicity of the new prodrugs is much lower compared to parent PMEA 1, though their values of antiviral activity are in a similar range (Table 1).…”

“…[5] 2-Aminobenzyl alcohols were synthezised by reduction of the corresponding anthranilic acids with lithium aluminiumhydride (4-Me: 61%, 6-Me: 71% yield). 7-Me-2-aminobenzyl alcohol was prepared by reduction of 2-amino-acetophenone with sodium borhydride (99% yield).…”

“…[4] We already reported on the synthesis and characterization of cycloSal-and cycloAmb-PMEA prodrugs. [5] The cycloSal derivatives show very low hydrolysis half-lives limiting their antiviral potency. The cycloAmb compounds show 832 U. Görbig et al higher hydrolysis half-lives, partially in optimal ranges.…”

“…But their hydrolysis led to a quite stable hydrolysis intermediate 8 ( Figure 1) that delivered PMEA very slowly, so their antiviral potency was also limited. [5] Here, we present novel cycloAmb-PMEA prodrugs with new substitution patterns in order to destabilize the hydrolysis intermediate and accelerate the delivery of PMEA 1 to achieve higher antiviral activity.…”

Prodrug Approaches of Nucleotides and Oligonucleotides

“…The applicability of cyclosaligenyl derivatives as pronucleotides has been tested with several anti-HIV nucleosides: 3´-deoxythyminine (ddT), d4T [75][76][77], 2´,3´-dideoxyadenosine (ddA) [78,79], FdU [80,81], AZT [82] and 9-[2-phosphonomethoxyethyl]adenine (PMEA) [83]. In vitro antiviral activity has been shown to correlate with the hydrolytic stability or the pronucleotide: 3-and 5-methyl substituents on the benzene ring enhance the antiviral activity against HIV-1 and HIV-2 infected cells.…”