Nucleoside Acyclic Phosphates

1 Nucleoside Acyclic Phosphates. 2-Chloro-2,A-dioxo-3-methyltetrahydro- 

3 -fluoronucleosides into their 5 -monophosphates has been accomplished using whole cells of the bacteria Erwinia herbicola and A-nitrophenyl phosphate as a phosphate donor. Additionally, conv rsion of the monophosphates to the 

Adenosine 5 -0-monophosphate has been oxidised to the corresponding N-l-oxide (A) (53Z yield) using potassium hydrogen persulphate in aqueous 

Papers which report the synthesis of dinucleoside monophosphates or their analogues as model studies for oligonucleotide synthesis are covered in section 4. 

1 Nucleoside Acyclic Phosphates - It is well established that most nucleoside analogues become biologically active as a result of cellular conversion to phosphomonoesters. For this reason there has been increasing interest in the synthesis of nucleoside phosphotriesters and in some cases, i osphodiesters which might act as membrane soluble pro-drugs of the bioactive nucleotides. The diethyl-, dipropyl- and dibutyl-phosphates (1) of 2, 3 -dideoxy-3-deaza-adenosine have been synthesis and shown to possess anti-HIV-1 activity at non-cytotoxic doses. Phosphate triester derivatives of the anti-leukaemic nucleoside nmbi/io-cytidine have 

More complex esters of 3 -azido-3 -deoxythymidine (AZT) carrying carboxylic ester-containing side chains, have been prepared and evaluated as potential anti-HIV agents. In particular, the Ms-(methyl lactyl) triester (S) was shown to be more selective in its anti-viral 

A series of aryl b(s-(nucleoside-5 -yl)phosphates in which the nucleosides are either 2, 3 -dideoxy (d2) or 2, 3 -didehydro-2, 3 -dideoxy (d4) has been prepared by coupling the nucleoside moieties together using a standard phosphotriester approach. Only the 4-(methyl-sulphonyOphenyl derivatives of d4T (13) and d2A (14) showed anti-HIV activity that was comparable with the parent nucleosides. The activity of these compounds can be explained by uptake of the triesters into cells followed by a slow release of the niKleoside and nucleotide. A similar strategy has been adopted by Meier and Huynh-Dinh based on the recent observe- 

Nucleoside phosphonate analogues continue to attract attenticm as therafteutic nucleotide analogues since the phosphorus-carbon bond is resistant to enzymatic hydrolysis. A general procedure has been develo )ed for the synthesis of S -C- hos hononie(hyl nucleosides (24) which are isosteric with nucleoside 5 -monophos ihates. Phosjrfionate derivatives of the dide- 

HIV-1 activity. The key synthetic steps involved an Arbusov reaction between triethylphos-phite and 3,5,6-trideoxy-6-iodo-l, 2-O-isopropylidene-a-D-e/yrtro-hexafiiranose (31), followed by condensation with the appropriate nucleoside base. 

Organophosphorus Chemistry, Volume 33 The Royal Society of Chemistry, 2003 

The use of 2-cyano-l-f-butylethyl- and 2-cyano-l-(l,l-diethyl-3-butenyl)ethyl-phosphorimidazolidite as new phosphitylating reagents has been reported for 

P-Heteroaryl-substituted ethanols, pyridine 2-ethanols and pyridine 4- 

4-Dinitrophenol has been shown to be a remarkably efficient activator in the reaction of P(III) amides with nucleosides to give P(III) triesters in excellent yield. Using 2,4-dinitrophenol, the diastereomerically pure fluorophos-phoramidite of 5 -dimethoxytritylthymidine reacted with 3 -dimethoxytrityl- 

The 5 -phosphoramidite of the novel bicyclic nucleoside (14), restricted to an S-type conformation, has been synthesised in eight steps via double inversion of configuration at the C4 position of protected l-(3 -deoxy-p-D-psicofuranosyl)uracyl and introduction of an azide moiety. The secondary amino group at C4 permitted the subsequent incorporation of (14) into oligonucleotides via a 5 -3 directed variation of the standard phosphoramidite approach for synthesis of oligonucleotides. Thermal denaturation studies showed rather large decreases in duplex stabilities toward complementary DNA and RNA.  

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Nucleoside Acyclic Phosphates. - 2.1.1 Mononucleoside Phosphate Derivatives. A preliminary study on a novel solid phase reagent (Scheme 1) for the capture phosphorylation of nucleosides has been described. The 1 % cross-linked divinylbenzene-polystyrene copolymer, containing cyanoethoxy iV,AT-diisop-ropyl phosphine was used for the selective phosphorylation of uridine to 5 -uridine monophosphate (UMP) in 67% yield. ... 

McGuigan and coworkers [19] prepared a range of acyclic 5 -dialkyl phosphate triester derivatives of the anticancer drug ara-C (11, B = cytosyl, R = Et, n-Pr, n-Bu, n-pentyl or n-hexyl). These triesters inhibited DNA synthesis and their efficacy improved with increasing lipophilicity. This result suggested that these triesters were membrane permeable however, their mechanism of inhibition of DNA synthesis was unresolved. In a similar study, inhibition of DNA synthesis also increased as the lipophilicity of the phosphate triester of the anti-viral nucleoside ara-A (11, B = adenyl, R = Et, n-Pr, n-Bu or n-pentyl) increased [20]. The dibutyl phosphinate analogue... 

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