Antiviral activities nucleoside phosphonates

De Clercq E, Descamps J, De Somer P, Holy A (1978) (S)-9-(2,3-Dihydroxypropyl)adenine an ahphatic nucleoside analog with broad-spectrum antiviral activity. Science 5 563-565 De Clercq E, Holy, A (2005) Acyclic nucleoside phosphonates a key class of antiviral drugs. Nature reviews 4 928-940... 

Wyles DL, Schooley RT, Kaihara KA, Beadle JR, Hostetler KY (2008) Anti-hepatitis C virus repli-con activity of alkoxyalkyl esters of (S)-HPMPA and other acyclic nucleoside phosphonates. In Abstracts of the 21st international conference on antiviral research, Montreal, QC, Canada, 13-17 April 2008. Antiviral Res 78 A21, no 15... 

New types of acyclic nucleoside phosphonates (408-412) have been obtained using a multistep synthetic approach based on N-1, O- and S-alkylations of 4-and 2,4-substituted 6-hydroxy and 6-mercaptopyrimidines with diisopropyl 2-(chloroethoxy)methylphosphonate and (R) or (S) - [2-(diisopropylphos-phonyl)methoxy] propyl tosylate. Inhibitory activity against viruses of both the nucleoside phosphonates and the related phosphonic acids was investigated. It was found that the 6[2-(phosphonomethoxy)ethoxy]pyrimidines must bear an (unsubstituted) amino group concomitantly on both C-2 and C-4, or an amino on C-2 and an OH group on C-4, to display antiviral activity. Alkyl ethers are preferred over alkyl thioethers. The compounds of the 6-[2-(phos-phonomethoxy)ethoxy] and 6-[2-(phosphonomethoxy) propoxy]pyrimidine... 

Methodologies to create functional and topological diversity in libraries of nucleoside phosphoramidates have been improved by the use of parallel solid-phase synthesis. A representative 600-member library of dinucleoside phosphoramidates (16) and tri-nucleoside phosphoramidates (17) was synthesised from CGP-support-bound di- and tri-nucleoside H-phosphonates (5 -DMT protected) and selected amines. The library was screened for antiviral activity against HBV and some of its members showed potent activity. ... 

Balzarini and De Clercq have reported a novel subclass of acyclic pyrimidine nucleoside phosphonates (81a-j) and (82a-f) that are endowed with inhibitory activity against both DNA and retroviruses. Extensive SAR studies indicated that the 6-[2-(phosphonomethoxy)ethoxy] pyrimidines must bear an unsubstituted amino group concomitantly on both and C, or an amino on and an OH group on C in order to display antiviral activity. In addition it was found that alkyl ether derivatives are preferred over alkyl thioethers. The reaction of the acyclic 6-chloropurine nucleoside derivatives with guanidine in a DMF solution in the presence of BABCO yielded the 6-guanidinopurine parents, which were subsequently alkylated with diisopropyl 2-chloroethoxymethylphos-phonate in the presence of CS2CO3 to yield the acyclic nucleoside phosphonates... 

Alternative antiviral agents for the treatment of drug-resistant herpesviruses are the acyclic nucleoside phosphonate analogs. The lead compound of this new series of antiviral molecules is cidofovir [(S)-l-(3-hydroxy-2-phosphonylmethoxypropyljcytosine] (HPMPC), which has a broad-spectrum antiviral activity in vitro and in vivo against several DNA viruses. Cidofovir has been approved for the treatment of CMV retinitis in AIDS patients, and it has also been shown to be effective in the treatment of persistent mucocutaneous infections caused by ACVr HSV and ACVr/PFAr HSV (6,7). 

Metal ion complexes of antivirally active acyclic nucleoside phosphonates as nucleotide analogs 04CSR191. 

Acyclic nucleoside phosphonates have been shown to display a wide variety of biological activity. A review of the antiviral activity of acyclic nucleoside phosphonates has been published. ... 

Hostetler KY (2009) AlkoxyaUcyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity current state of the art. Antiviral Res 82 A84-A98... 

A series of nucleosides monophosphates have been evaluated as selective P GXPRT inhibitors. Among them, the cycfrc phosphonates (R)-cycfrc-HPMPG 154 and (S)-cyclic-HPMPG 58 (see Section 3.1, Antiviral activities) are representative stmctures (Figure 19). 

Fridland and coworkers have shown that the bis(pivaloyloxymethyl) esters of three acyclic nucleoside phosphonates, including PMEA, have improved antiviral activity and selectivity when compared with the corresponding phosphonic acid [65]. Using radiolabelled material, in cells the PMEA prodrug (47, R = Bu ) hydrolyzed rapidly to PMEA after which it was phosphorylated to the active diphosphate. In contrast, the prodrug had a half-life of over 24 h at pH 2,0, suggesting that it may be stable in gastric... 

The discovery of antiviral activity of oligo(nucleoside methane-phosphonate)s (44) and oligo(nucleotide phosphorothioate)s (45-47), so far chemically prepared by the nonstereocontrolled methods, attracted the attention of several research establishments to the search for stereospecific synthesis of those classes of oligonucleotide analogs. Since their routine synthesis via phosphoramidite or any other approach leads to the mixture of m diastereoisomers, the question may be asked whether desired antiviral activity is owing to all m components of diastereo-isomeric mixture or to the fraction possessing the proper sense of chirality at each modified phosphate. Moreover, since the seminal works of... 

Starting from (641), have been reported by Peyrottes and co-workers (Scheme 159). These derivatives were designed as structural analogues of Adefovir (PMEA), a well-known acyclic nucleoside phosphonate used for the treatment of HBV infections. The newly obtained derivatives were assayed in various cell lines for antiviral activity against a wide variety of DNA and RNA viruses, however, none of them revealed a significant effect. ... 

A series of novel acyclic nucleoside phosphonates (819) with various nucleobases in the oo-position and variously substituted in the p-position of alkylphosphonate chain, have been prepared by Hockowa et al. Several derivatives exhibited antiviral activity against HIV and vaccinia virus, HSV-1, HSV-2, VZV and CMV, although the parent unsubstituted derivatives were anti vitally inactive. Adenine as a nucleobase and the p-methyl group attached to the alkylphosphonate chain proved to be a prerequisite to afford pronounced antiviral activity. " ... 

Hexade(ylo Q ropyl prodrugs of acyclic nucleoside phosphonates (56 and 57) were also synthesized and evaluated for their antiviral activities." Among them, 57b was found most potent against DNA vimses, but none of these compounds to be inhibitory against RNA viruses. The highly lipophilic hexadecyclojgrpropyl moiety is believed to enhance antiviral activities due to the better cellular permeability of the prodrug. 

Van Poecke et al. prepared a series of 5-(hetero)-aryl-modified nucleoside phosphonates (66) by an eight-step synthetic route involving a Wittig reaction and Suzuki couplings, protections and deprotections. These analogues showed promising antiviral activity. 

The phosphonate acyclic nucleosides, 174-177 (Fig. 30), are broad spectrum antiviral agents active against DNA and retroviruses [207]. They are a family of structurally related compounds of which 175-177 show significant anti-HIV activity [208]. The mechanism of action of 175-177 remains to be elucidated. For the structurally related 174, it has been shown that it can, as such, be incorporated by the cells. Then, it is converted to the mono and diphosphoryl derivatives by cellular enzymes. The latter diphosphorylphosphonate, which can be considered as an analog of nucleoside-5 -triphosphate, may be the active form of the molecule, which inhibits viral DNA synthesis at concentrations which are by several orders of magnitude lower than those required for inhibition of cellular DNA synthesis. Similarly the anti-HIV activity of 175 may be attributed to a specific inhibition of the viral RNA-directed DNA synthesis. 

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