NewCycloAMB-Nucleoside Phosphonate Prodrugs

Abstract

cycloSal- and cycloAmb-nucleoside phosphonate prodrugs of PMEA were synthesized and characterized. Each of these compounds showed different disadvantages in hydrolysis. Thus, a new series of cycloAminobenzyl(cycloAmb)-PMEA prodrugs was synthezised and studied with regard to their hydrolysis properties and biological activity.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…90 In these molecules, the cyclo Sal phenolic oxygen atom is replaced by a nitrogen hypothesizing that the less electronegative nitrogen would reduce the electrophilicity of the phosphorus atom and consequently increase the stability of the prodrug. The first attempt to prepare the cyclo Amb-PMEAs, using the reaction sequence shown in Scheme 61, led to the isolation of the targeted compounds 211 (Scheme 62) in very poor yield (3–7%).…”

“…First attempts to prepare cyclo Sal-PMEAs 209 , directly from the diethyl ester of PMEA 48 , without protection of the exocyclic amino group, led to a complex mixture of reaction products. 90 To overcome this problem, the diethyl ester exocyclic amino group was blocked by a monomethoxytrityl protective group (Scheme 61 ). Treatment of the intermediate with trimethylsilyl bromide then gave the bis(trimethylsilyl) ester that was immediately converted into the corresponding dichloride 208 using PCl 5 .…”

“…Unexpectedly, cyclo Sal-PMEA derivatives 209 appeared to be unstable especially in acidic conditions (pH = 2) and led to the design of possibly more stable cycloaminobenzyl-PMEA (i.e., cyclo Amb-PMEA) phosphoramidates 211 . 90 In these molecules, the cyclo Sal phenolic oxygen atom is replaced by a nitrogen hypothesizing that the less electronegative nitrogen would reduce the electrophilicity of the phosphorus atom and consequently increase the stability of the prodrug. The first attempt to prepare the cyclo Amb-PMEAs, using the reaction sequence shown in Scheme 61 , led to the isolation of the targeted compounds 211 (Scheme 62 ) in very poor yield (3–7%).…”

Medicinal Chemistry of Nucleoside Phosphonate Prodrugs for Antiviral Therapy

“…The reduced antiviral activity was attributed by the authors [61] to the slow release of PMEA (8) from the cycloAmb-PMEA, the rate-limiting step being the cleavage of the intermediate benzyl phosphonate ester II. To achieve higher antiviral activity, different cycloAmb-PMEA derivatives with new substitution patterns were reported [62]. However these new prodrugs failed to accelerate the decay of the hydrolysis of the intermediate II , presenting only a slightly improved antiviral activity when compared to the previous cyclo-Amb prodrugs.…”

Prodrug approaches to improving the oral absorption of antiviral nucleotide analogues

“…They have illustrated the utility of this approach using various nucleoside and nucleotide analogues including acyclovir [69], 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir) [70], 2′,3′-dideoxyadenosine (ddA) [71], 2′,3′-dideoxy-2′,3′-didehydroadenosine (d4A) [71], 5-[(E)-2-bromovinyl]-2′-deoxyuridine (BVdU or brivudin) [72,73], 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T) [74–79] and carbocyclic 3′-azidothymidine analogues [80]. …”