Nucleoside polyphosphates

Treatment of nucleoside and deoxynucleoside 5 -monophosphates with inorganic diphosphonate in aquo at pH 6 at elevated temperatures has been reported to afford the corresponding 5 -phosphonylphosphates (112) in yields of up to 70 xhe compounds were characterized largely using 3lp n.m.r. spectroscopy. 

5-Vinyl- and 5-ethynyl-2 -dUTP have been prepared by treating the unprotected nucleosides with phosphoryl chloride at ice temperature in the 

In the continuing search for isozyme-specific inhibitors of rat methionine adenosyltransferases, the covalent conjugate (119) of L-ethionine and adenylyl imidodiphosphate has been prepared. 23 in the synthetic route, protected adenosine was converted to its 5 -aldehyde, condensed with vinylmagnesium bromide, and hydroboration, tosylation and condensation with L-homocysteinate served to introduce the L-ethionine moiety, the 5 -hydroxy group then being phosphorylated by Tener s method and converted conventionally to the p, y-imidotriphosphate. 

The epimeric mixture of (119) obtained was a powerful inhibitor of the rat enzymes from normal and hepatoma tissues, acting as a multisubstrate inhibitor against both ATP and L-methionine. 

N-methylimidodiphosphate. While (125) was a substrate for creatine kinase, (126) showed no detectable inhibitory properties. 

2 Nucleoside Polyphosphates. - The preparation of the phosphonate analogues of IpJ and IpsI (130) and (131) has been described. Various methods for the efficient synthesis of these compounds have been examined. The most convenient method employed tris(imidazolido)phosphate and inosine 5 -methyl-enediphosphonate, which had been prepared from 2, 3 -isopropyledeneinosine and methylenebisphosphonic dichloride.  

Three novel bisubstrate analogues (133a-c) acting as potent inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase have been synthesised and used in the co-crystallisation of the kinase. These compounds were synthesised by coupling adenosine nucleotides (AMP, ADP and ATP) to 6-hy- 

Reiner, E. Kvasyuk and W. Pfleiderer, Helv. Chim. Acta, 2000,83, 3053. 

Dabkowski, I. Tworowska, J. Michalski and F. Cramer, Tetrahedron Lett., 2000, 41,7535. 

Boesen, C. Madsen, U. Henriksen and O. Dahl, J. Chem. Soc., Perkin Trans. 1, 2000,2015. 

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 

The triphosphate (80) of a carbocyclic nucleoside has been prepared as a racemate in 

Symmetrical dinucleoside S -pyrophosphates (82) have been prepared in high yields ( 80%) from the free acid of the nucleoside S -phosphate. This one-pot procedure is most efficient when performed in DMF or DMSO using about four equivalents of triphenylphosphine and 2,2 -dipyridyldisulphide as the coupling agent and a large excess of N-methylimidazole as the catalyst. The cap portion (83) of messenger RNA has been synthesised in 37% yield by 

Mn ion-catalysed pyrophosphate bond formation between 7-methyIguanosine S -phosphorimi- 

hydrolysis of the phosphorimidazolide was predominant. The role and effect of varying 

A very mild method has been described for the preparation of nucleoside 

5 -bisphosphates.Under strictly anhydrous conditions pyrophosphoryl tetrakistriazolide reacts with nucleosides to form a pyrophosphate ring structure which bridges the 3 - and 5 -hydroxy functions. Hydrolysis of this intermediate in the presence of triethylamine opens the pyrophosphate to form the 3, 5 -bisphosphate. The procedure is particularly suited to the preparation of acid labile nucleotides and has been applied to the synthesis of blsphosphates derived from N-2,3-etheno-2 -deoxyguanosine, 0-2-ethyl-2 -deoxy-thymidine and 0-4-methyl-2 -deoxythymidine. 

In an attempt to exploit the mannose-6-phosphate receptor system to facilitate the uptake of nucleotides, nucleoside adducts of D-mannose-6-pyrophosphate have been prepared. P -(5-Iodo-2 -deoxyuridine)-5, P -D- 

Prominent amongst the many nucleoside polyphosphates (nucleoside anhydrides) which have been isolated and studied are triphosphate monoesters of type (10.101a) and diphosphate esters of type (10.101b) (R = nucleoside or other organic groups). Many anhydrides of these types have been identified and isolated from natural sources, and some have been obtained by laboratory synthesis. 

One of their most important properties is their ability to phosphorylate proteins, particularly enzymes (Chapter 11). 

Biochemically important examples are provided by various energy-carrying compounds. These are, for type (10.101a), ATP (11.10) and other ribonucleotide triphosphates (11.29) and for type (10.101b), NAD, FAD and co-enzyme-A (11.23), (11.28) and (11.20). 

Chemical Synthesis.—The phosphorimidazolidate method for the preparation of nucleoside di- and tri-phosphates has been re-examined and extended. For instance, ATP may be prepared either by activating ADP with carbonyl di-imidazole and treating the resulting phosphorimidazolidate with inorganic 

Chemical Synthesis.—Di-n-butylphosphinothioyl bromide (45) reacts readily with C.-Y. Lee and C.-J. Johansson, Analyt. Biochem., 1977, 77, 90. 

Some nucleoside polyphosphates are very conveniently prepared using enzymic methods. For instance, the reaction  

Johnson, M. MacCoss, and S. Narindrasorasak, Biochem. Biophys. Res. Comm., 1976, 71, 144. 

Analyt. Biochem., 1976, 76, 361. 

On treatment with DCC, ATP forms adenosine trimetaphosphate (53). Treatment of (53) with a nucleophile opens the ring to give the y-substituted ATP derivative, 

The first examples of supercharged nucleotide analogues (85-87) have been described, in which methylenebisphosphonic acid containing an additional ioni-sable acidic function has been incorporated into p,y-bridged derivatives of adenosine triphosphate. The compounds and their protected precursors were obtained following acid-catalysed reaction of the respective precursors (88-90) with adenosine 5 -phosphoromorpholidate in pyridine in yields of 80,75 and 25%. 

A carbocyclic NAD(+) analogue (91) incorporating a methylenebisphospho-nate linkage in place of the natural pyrophosphate has been prepared as an inhibitor of ADP-ribosyl cyclase which is resistant to non-specific phosphatase degradation.The analogue 91 was obtained in 25% yield following a Poulter coupling of the precursor 92 with adenosine 5 -methylenebisphosphonate. 

UDP-pyridoxal 93 has been prepared in good yield from uridine-5 -phosphoro-morpholidate and pyridoxal phosphate and found to activate the enzyme carbamoyl phosphate synthetase (CPasell) which is involved in pyrimidine biosynthesis.  

Several novel diadenosine 5, 5 -P-l,P-4-tetraphosphate (AppppA) analogues (94 95) and an adenosine tetraphosphate analogue (%) have been prepared as competitive inhibitors of ADP-induced platelet aggregation. Among the various analogues, the P-2, P-3-monochloromethylene AppCHClppA was found to be particularly active. 

The stable bisubstrate ligands 109 of phosphoglycerate kinase (PGK) in which adenylate is attached to non-scissile 1,3-bisphosphoglycerate analogues have been described. The analogues form high-affinity complexes with PGK as determined by H NMR. 

In order to increase the chemical stability of ATP derivatives that possess long thioether tethers, the 1-thiotriphosphate analogues (86) have been prepared from 2-thio-adenosine. These compounds were fourfold more stable to pig pancreas type I ATPDase than ATP. They were also more potent than ATP at stimulating intracellular response and were established as new insulin secreta- 

ATP analogues substituted at the C2 (87) or C8 (88) positions with electron-donating groups such as ethers, thioethers or amines have been synthesised and evaluated for their potency at inducing P2Y i receptor mediated activation of the phospholipase C and subsequent intracellular Ca release. These analogues were also evaluated for their chemical stability to the hydrolytic nucleoside triphosphate diphosphohydrolase enzymes. Adenine derivatives 

The syntheses of the 5 -phosphoramidates and 5 -diphosphates of 2 -0-allyl-P-D-arabinofuranosyl-uracyl, -cytosine and adenine (96) have been described. 

These nucleotide analogues have been evaluated for inhibition of the nucleotide reductase enzymes but exhibited no activity.  

In order to develop a purification procedure of thymidine 5 -diphosphate-glucose-4,6-dehydratase based on affinity chromatography, novel activated thymidine diphosphate analogues that display high affinity for the dehydratase have been synthesised. These diphosphate analogues have been derived from 

GTP is an essential component in protein synthesis, and it has been shown recently that another guanosine polyphosphate, guanosine 3, 5 - 

Adenosine 5 -hypophosphate (23), an analogue of ADP, can undergo phosphorylation by PEP and pyruvate kinase to yield (24). Adenylate kinase which catalyses the scission of the bond between the a and j8 phosphorus atoms in ADP is, not surprisingly, inhibited competitively by (23). 

The adenosine diphosphate derivative (98), a recently discovered metabolite produced during tRNA splicing, has been synthesised by reaction of (99) with (100) in the presence of silver acetate. Its spectroscopic properties are also reported. 

The triphosphate (101) has been synthesised by reaction of the free nucleoside with phosphoryl chloride, followed by pyrophosphate. It was found to be an 

The triphosphate (102) has been prepared from the CDI-mediated condensation between pyrophosphate and corresponding nucleoside S -monophosphate and has been designed for the photoaffinity labelling of HIV-reverse transcriptase. The analogue is relatively stable but upon irradiation at 365 nm a highly reactive carbene moiety is generated. 

The triphosphate 7V-2-(p-n-octylphenyl)-2 -deoxyguanosine has been synthesised by reaction of the nucleoside 5 -monophosphate with tetrabutylammonium pyrophosphate in HMPA. The compound displays selective inhibition of DNA polymerase a, compared to S and e, but is less selective than the known inhibitor N2-(n-butyl)dGTP. 

The 5 -methylenephosphonate derivative of ATP (106) has been prepared by condensation of the corresponding phosphonate with pyrophosphate using CDI. The analogue was found to be a substrate for T3 RNA polymerase. 

Interest in guanylyl 3, 5 -dipyrophosphate [ppGpp (23)] has continued. This nucleotide is implicated in RNA synthesis in E. coli, and ppGpp 

An analogue of ATP (24) in which a stable nitroxide free radical is attached through a sulphur atom to the 6-position of the purine ring will 

Standard-free-energy maps for the hydrolysis of ATP as a function of pH and bivalent cation concentration have been published. Quantum mechanical calculations show that ATP should have a tendency to adopt a folded conformation, in agreement with crystallographic data.  

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Moffatt, J.G. Khorana, H.G. (1961) Nucleoside Polyphosphates. XII. The Total Synthesis of Coenzyme A. Journal of the American Chemical Society, 83, 663-675. 

In many prokaryotes, PolyP is a direct phosphorus donor for biochemical reactions due to the action of enzymes such as polyphosphate-glucose phosphotransferase and NAD kinase. Polyphosphate kinases and PolyP AMP phosphotransferase link nucleoside-polyphosphate and inorganic PolyP. Polyphosphate kinases 1 and 2 can use PolyPs for the synthesis of different nucleoside triphosphates. 

I. S. Kulaev, T. P. Afanas eva and M. P. Belikova (1967a). The localization of inorganic polyphosphates and nucleoside polyphosphates in cells of the yeast Endomyces magnusii (in Russian). Biokhimiya (Moscow), 32, 539-546. 

Nucleoside 5 -monophosphate Nucleoside 3, 5 -bisphosphate Nucleoside 5 -triphosphate Nucleoside polyphosphates... 

The quantitative separation of phosphorus acids and esters by ion-exchange chromatography has been reviewed. The separation of nucleoside polyphosphates by anion-exchange chromatography and the affinity chromatography of enzymes on immobilized adenosine monophosphate have also been described. 

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