Triphosphate analogues

Inhibitors of HIV Reverse Transcriptase (RT-HIV) Replacement of the oxygen by a difluoromethyl in triphosphate analogues of carbovir, is accompanied by a one order-of-magnitude loss in anti-RT activity, while the plasma half-life is fifty times enhanced (Figure 7.19). ... 

Novel 2, 3 -deoxy fluorescent 3 -C-branched thymidine 5 -triphosphate analogues have been prepared and employed as potential terminators in DNA-sequencing reactions. The amino-nucleotide derivatives (105), (106) have been dye-labelled at the aliphatic amino-group with the oxazine dye JA242. ... 

Novel 2 -modified nucleoside triphosphate derivatives incorporating imidazole, amino or carboxylate pendant groups attached to the 5-position of pyrimidine base through alkynyl and alkyl spacers (115) have been synthesised. In one reported procedure, the appropriately protected modified nucleoside was phosphorylated with POCI3 in triethylphosphate in the presence of 1,8-bis(dimethylamino)naphthalene. The phosphorochloridate intermediate was then condensed in situ with tri-n-butylammonium pyrophosphate to yield the protected triphosphate analogue that was then deprotected. In another... 

The nucleoside 3 -triphosphate analogue 117 conjugated to the p-aminophe-nylethylamino linker has been obtained from EDCI-mediated coupling of the... 

In an attempt to develop improved anti-HIV agents many nucleoside 5 -triphosphate analogues have been synthesised and studied as inhibitors of HIV reverse transcriptase. The... 

Previous work has revealed the thymidine triphosphate analogue to be a substrate for human placenta DNA polymerase a, and AMV and HIV reverse transcriptases. A one-pot procedure has been developed for the preparation of a-methylphosphonyl-p, y-diphosphates of thymidine (86) and... 

Some carbocyclic nucleoside phosphonates have been described. There has been a further report on compounds of type 208 (see Vol. 28, p. 291), with both purine and pyrimidine bases. Although initially made as racemates, a precursor diol could be resolved by enantioselective acetylation using a lipase and vinyl acetate.The triphosphate analogues 209 (B=Gua, Ade) have been made from the previously-described monophosphonates (Vol. 29, p. 285), and the cyclopropyl-fused diphosphate analogues 210 (X=CH2 and O) were also reported, along with their enantiomers. Trani-compounds of type 211 (n=l-3) have been made as racemates,and so have the related cw-isomers (n=l or 2). ... 

The 3 -0-phosphonomethyl compound 203 has been prepared by alkylation of 0-3 of thymidine, and was converted into the triphosphate analogue 204 by reaction with tributylammonium pyrophosphate, previously activated by car-bonyldiimidazole. Initial reaction of 203 with carbonyldiimidazole led to the formation of a dimeric pyrophosphonate of 203. Similar chemistry was also carried out on a-thymidine, and the substrate properties of the products 203 and its a-anomer towards DNA polymerases were studied. ... 

Scheme 51 Synthesis of bismethylene triphosphate analogue 259 of nucleosides...

Scheme 52 Preparation of hydrolytically stable triphosphate analogues 266 of nucleosides...

The first asymmetric synthesis of two phosphatidylinositol 3,4,5-triphosphate analogues (24) and (25) that are resistant to the 3-phosphatase PTEN and their biological activity, has been described. 

A solid-phase reagent (8) has been described for the synthesis of P-triphosphate derivatives,and the benzodioxaphosphorinone, the P(iii) analogue of (6), which has previously been used for the synthesis of oligonucleotide-triphosphate derivatives, has now been used to synthesise dinucleotide tetra- and pentaphosphonates. The asymmetric bismethylene triphosphate analogue (9) has been used for the synthesis of bismethylene triphosphate analogues of nucleosides. ... 

The N-methylimido analogue (135) of ADP has been synthesized, and it could be converted enzymically to the triphosphate analogue. The pj-methylimidO triphosphate was also rnade. Blackburn s group have described the synthesis of the Pl, P -dithioderivative (136) of diadenosyl tetraphosphate (ApaA), and some phosphonate analogues (137), 192 and also phosphonate and thiophosphate analogues of ApsA.193... 

Various triphosphate analogues have been reported. Eckstein s group has prepared the 1,3-dithiotriphosphate of AZT, the first example of this modification, and also the 1,1-dithioderivative of TTP.226 xhc same workers have also made the 2 epimers of 1,2-dithio-GDP, and converted them to the four diastereomers of l,2-dithio-GTP.227 jhe a,p-methylene, fluoromethylene and difluoromethylene analogues of dATP and TTP have been synthesized,22S as has the p.y-difluoromethylene analogue of AZT triphosphate, the phosphonate proving to be some 30 times less inhibitory towards HIV reverse transcriptase than the triphosphate.229... 

There appears to be a relationship between the antiviral activity and the electron-withdrawing capacity of the substituents in the S-position of the nucleoside analogues as evidenced by the decrease in the antiviral activity when the methyl moiety was replaced (CF3, F > I > Br > CH3). These differences may be related to their substrate activity for thymidine kinase, which is required for activation, or to the differences in metabolic conversion to the di- or triphosphate, or to the relative afflnity of the nucleoside triphosphate analogue for the reverse transcriptase. 

Replacement of the uracil moiety of the 3 -azido nucleoside analogue 1 with the cytosine to form 7 did not affect its antiviral activity however, when the substituent on carbon-5 of the cytosine moiety was either fluoro 8 or methyl 9, the antiviral activity was markedly reduced. This could be explained if these 3 -azido-2, 3 -dideoxycytidine analogues were required to be deaminated by deoxycytidine deaminase for which the 5-methyl or 5-fluoro analogues are not substrates. Other possibilities include differences in metabolic conversion to the di- and triphosphates analogues, as well as the relative affinities of the triphosphate analogues for the reverse transcriptase. 

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