Nucleoside phosphonates Nucleosides

However, acyclic nucleotide analogs (acyclic nucleoside phosphonates) have been developed, which carry one phosphonate moiety and require only the two subsequent phosphorylation steps (De Clercq et al. 1978). Independent of virus-encoded kinases, they display a broader spectrum of efficacy. This class comprises important drugs against HIV (tenofovir) and HBV (adefovir, tenofovir), as well as cidofovir, which is approved for use against CMV retinitis, but also displays an exceptionally broad efficacy profile against many herpesviruses, adenovirus, poxviruses, and papillomaviruses (De Clercq and Holy 2005). 

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... 

TACV Triacyclic analogue of acyclovir TGCV Triacyclic analogue of ganciclovir ANP Acyclic nucleoside phosphonate TK Thymidine kinase... 

Fig. 2 Structural formulae of acyclic nucleoside phosphonates (anti-DNA virus and/or retrovirus agents)...

The acyclic nucleoside phosphonates (ANPs) can be considered as nucleotide rather than nucleoside analogues, in that, besides the purine or pyrimidine base, they contain an (acyclic) sugar moiety to which a phosphonate is attached. In these nucleotide analogues (Fig. 2), the phosphoric ester grouping (= P-O---C-----) is... 

The prototype member of the ANPs is (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine (HPMPA) (Fig. 2), first described for its broad-spectrum anti-DNA virus activity in 1986 (De Clercq et al. 1986). Then followed by the description of various other acyclic nucleoside phosphonates in 1987 (De Clercq et al. 1987). At present three acyclic nucleoside phosphonates have been licensed for clinical use cidofovir, adefovir, and tenofovir (Fig. 2). 

Appropriately designed prodrugs, for example, phosphonoamidates (Lee et al. 2005), may allow acyclic nucleoside phosphonates such as tenofovir to be specifically targeted at tissues, that is, lymphatic tissue, where the virus (i.e., HIV) replicates. This principle has been recently extended to another nucleotide analogue, GS-9148 (Cmiar et al. 2008) and its phosphonoamidate prodrug, GS-9131 (Ray et al. 2008). 

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... 

Figure 6 Acyclic nucleoside phosphonates (ANPs) 9-(2-phosphonylmethoxy-ethyl)-adenine (PMEA) and -2,6-diaminopurine (PMEDAP), (R)-9-(2-phosphonyl-methoxypropyl)-adenine (PMPA) and -2,6-diaminopurine (PMPDAP), (5)-9-(3-fluoro-2-phosphonylmethoxypropyl)-adenine (FPMPA) and -2,6-diaminopurine (FPMPDAP), and the bis(pivaloyloxymethyl) ester of PMEA [Bis(pom)-PMEA].

Balzarini J, Holy A, Jindrich J, Naesens L, Snoeck R, Schols D, De Clercq E. Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxy-propyl)-2,6-diaminopurine. Antimicrob Agents Chemother 1993 37 332-338. 

Srinivas RV, Robbins BL, Connelly MC, Gong Y-F, Bischofberger N, Frid-land A. Metabolism and in vitro antiretroviral activities of bis(pivaloylox-ymethyl) prodrugs of acyclic nucleoside phosphonates. Antimicrob Agents Chemother 1993 37 2247-2250. 

MRP4 is an ubiquitously expressed transporter with highest expression in the prostate where it can be localized to the basolateral membrane of tubuloacinar cells [149]. Schuetz and colleagues [150] demonstrated that high copy number and overexpression of MRP4 in a human T-lymphoid cell line was associated with cytotoxic resistance and increased cell efflux of an acyclic nucleoside phosphonate drug PMEA. Furthermore, these cells were more resistant to nucleoside analog... 

Pharmacology Tenofovir disoproxil, an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, inhibits the activity of HIV reverse transcriptase. 

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49-2). Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. 

DeClercq E. 2003. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev. 16 ... 

Substrates NSAIDS, fluoroquinolones, -lactam antibiotics, nucleoside phosphonates (Oatl),... 

Particularly promising as antiviral agents are the acyclic nucleoside phosphonates such as 9-[(2-phosphonylmethoxy)ethyl]adenine (PMEA, These compounds represent acyclic... 

Neyts J, De Clercq E (1994) Mechanism of acdon of acyclic nucleoside phosphonates against herpes vims replicadorr. Biochem Pharmacol 47 39 1. 

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... 

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... 

Hakimelahi has reported a novel strategy for the synthesis of N -purine acyclic nucleosides, in which the key step involves the reaction of [2-(p-methoxyphenyloxy)ethoxyl]methyl chloride and iV -tritylated nucleobases, followed by concomitant self-detritylation. 7-[(2-Hydroxyethoxy)methyl] guanine was phosphorylated by both HSV- and Vero-cell thymidine kinases to yield (92), and was found to have more potent cellular toxicity than acyclovir, while the adenine parent was phosphorylated by neither kinase. In addition, the N -adenine acyclic nucleoside phosphonate (93) was synthesised by alkylation of adenine with 3-bromopropionitrile to yield AT -(cyanoethyl)adenine, which upon... 

Stromberg has reported a detailed kinetic study of the pivaloyl chloride-promoted nucleoside TZ-phosphonate condensation step with a suitably protected nucleoside in the presence of differently substituted pyridines. He also investigated the stability of /Z-phosphonate nucleosidic dimers under various organic and aqueous basic conditions. Strong bases such as DBU and fluoride ions cleaved the dinucleoside ZZ-phosphonates rapidly, as also did a combination of protic solvent and a base. ... 

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