Mononucleoside Phosphate Derivatives

A series of S -phosphatidyl derivatives (11) of the potent anti tumour agent 

Nuc AZT, 5 -0-cordycepin or 2 -0-cordycepin R = C15H31CO, Ci3H27CO, C16H33 or C18H37 

A series of photo reactive and radiolabelled CMP-activated sialic acids have been prepared (17), ° all of which were found to be substrates for a-2,6- 

The analogue (20) has been designed as a hapten for the generation of catalytic antibodies with phosphodiesterase activity. The compound was synthesised by reaction of (21) with the phosphate diester (22) in the presence of the activating agent triisopropylbenzene sulfonyl chloride. 

The sulfamoylated AZT analogue (25) has been prepared as a membrane permeable analogue of AZT triphosphate. The sulfonylating agent (26) was prepared from diethyl hydroxymethyl phosphonate and chlorosulfonyl isocyanate. Compound (25) was a poor inhibitor of HIV reverse transcriptase but exhibited some anticancer activity. 

Organophosphorus Chemistry, Volume 32 The Royal Society of Chemistry, 2002 

The spiropentane mimics of 2 -deoxyadenosine and 2 -deoxyguanosine (5a,b) have also been synthesised as putative antiviral and anti-tumour agents. They were modest inhibitors of viral replication but could be activated by their conversion to lipophilic phosphoramidate pronucleosides, thus bypassing the first phosphorylation step required by their mode of action. However, the increase in potency was compromised by the amplification of their cytoxicity. 

Membrane permeant substituted-aryl phosphoralaninate derivatives (6) of the anti-HIV drug d4T have been synthesised. All of the derivatives were significantly more potent than d4T against HIV in cell culture however steric and electronic effects altered only slightly the inhibitor potency while the position of the mono-substituent had no obvious effect. 

Another prodrug form of acyclovir, l-O-hexadecylpropanediol-3-phos-phate-acyclovir (10), an orally bio-available lipid prodrug, has been synthesised from acyclovir using 2-chlorophenyldichlorophosphate in a phosphotriester approach and evaluated in vitro and in vivo against HSV-1. 

While the prodrug was less potent than acyclovir in in vivo assays, it was 2.4 times more active orally than its parent nucleoside.  

The chemical reactivity of 2 -deoxy-2 -thiouridine 3 -(p-nitrophenyl phosphate) (8), in which the 2 -hydroxyl is replaced with a 2 -thiol group, has been studied using P NMR and UV spectroscopy. Although similar to the hydrolysis of ribonucleotides, the rate of thiolate attack on the adjacent phosphatediester bond was determined to be 10 fold slower than that of the corresponding alkoxide. A study of the properties of 2 -deoxy-2 -fluorouridine 3 -(p-nitrophenyl phosphate) 

The adenosine 3 -0-phosphate esters 10 have been prepared as model compounds to study ribonucleotide cleavage with a number of different metal ions.  

The efficient syntheses of 2 -deoxyribonucleoside 3 -0- and 5 -0-phosphoro-dithioates 11 12 has been described.In each case phosphorylation of either the 3 -0- or 5 -0-protected nucleoside with 2-chloro-l,3,2-dithiaphospholane, followed by oxidation with sulfur gives the 2-thio-l,3,2-dithiaphospholane 13. Compound 13, upon DBU-catalysed reaction with 2-cyanoethanol gives 14 via loss of episulfide. Treatment with aqueous ammonia afforded the desired compounds 11 12. 

The preparation of nucleosidephosphorofluoridate (15), phosphorofluori-dothioate (16), and phosphorofluoridodithioate (17) monoesters in high yield from the corresponding nucleoside H-phosphonates has been described. The 

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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. ... 

Example 40 mononucleoside phosphotriester derivatives with 5-acyl-2-thioethyl bioreversible phosphate-protecting groups have been synthesized by Imbach and his associates [74a,b] in their research on intracellular delivery of 3 -azido-3 -dideoxythymidine-5 -mono-phosphate. 

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