Imidazole 5-amino nucleosides

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... 

From this observation of the inhibition by adenosine, and other observations, Newell and Tucker suspected the existence of a common synthetic pathway for adenosine and thiamine, and proved (with the help of a collection of mutants) that the bifurcation occurred after the 5-amino- l-(P-D-ribofura-nosyl)imidazole 5 -phosphate (46) step (Scheme 23). Finally, they found that 5-amino-l-(0-D-ribofuranosyl)imidazole (47), labeled with l4C in the imidazole ring, was incorporated into pyramine without significant loss of molar radioactivity by a mutant that is able to use this nucleoside (presumably after phosphorylation).53,54... 

From 133-tiiazines 23 and 5-amino-4-imidazole-carboxylic acids 24 a variety of purines and purine nucleosides 25 have been prepared via an inverse electron demand Diels-Alder reaction <99JA5833>. 

These polyphosphates can then phosphorylate nucleosides rather efficiently.48 If amino acids are present then AMP-amino acids are synthesized (see under peptide synthesis), but if imidazole is present then im-... 

Simultaneous peptide and oligonucleotide formation has been examined on a mixture of amino acid, nucleoside triphosphate, imidazole, and MgCl2 as reviewed in the previous section. In this reaction the oligonucleotide probably forms via nucleoside 5 -phosphorimidazolide 36). The yield of dinucleotide from ATP is up to 0.12%, the... 

Small quantities of the 5-amino-4-imidazolecarboxamide nucleotide were also isolated from the culture medium of Escherichia coli grown under sulfonamide bacteriostasis.i i This substance is considered to be an intermediate in purine biosynthesis, both in micro-organisms and in mammalian cells. In sulfonamide-inhibited cells and in the purine-requiring mutant of Escherichia coli, there is a block in the conversion of 5-amino-4-imidazole-carboxamide n-ribonucleotide to inosinic acid. The accumulated nucleotide in the bacterial cell is probably attacked by phosphatases this would explain why the nucleoside is the main metabolite. 

Almost all recorded purine syntheses from imidazoles involve the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-boxamides, carboxamidines, carboxamidoximes, nitriles and esters. The intermediates used for completion of the purine ring are much the same as have been used for Traube cyclization of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives, and cyclization generally occurs-under much milder conditions. This feature has been of special value in the synthesis of purine nucleosides from imidazole nucleoside precursors. The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to discuss and classify the various preparations largely in terms of the introduced 2-substituents. The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary very much between amino, oxo and thioxo. 

A sugar derivative related to the purine nucleosides, namely methyl 5-(adenin-l-yl)-5-deoxy-2,3-0-isopropylidene-j8-D-ribofurano-side, is formed by the reaction of methyl 5-amino-5-deoxy-2,3-0-iso-propylidene-jS-D-ribofuranoside with l-benzyl-5-cyano-4[(ethoxy-methylene)amino]imidazole, followed by removal of the benzyl group. On fusion, this compound rearranges to methyl 5-deoxy-2,3-0-isopropylidene-5-[(purin-6-yl)amino]-/8-D-ribofuranoside, which can also be obtained from the reaction of methyl 5-amino-5-deoxy-2,3-0-isopropylidene-/8-D-ribofuranoside with 6-chloro-9-(tetrahydropyran-2-yl)purine. In the same manner, methyl 5-amino-5-deoxy-2,3-di-0-p-tolylsulfonyl-/3-D-ribofuranoside reacts with 6-chloro-9-(tetrahydro-pyran-2-yl)purine to give methyl 5-deoxy-5-[9-(tetrahydropyran-2-yl)-purin-6-yl]amino-2,3-di-0-p-tolylsulfonyl-j8-D-ribofuranoside. With liquid ammonia, 5 -0-p-tolylsulfonyladenosine gives 5 -amino-5 -deoxyadenosine. On heating in p-dioxane, ring closure to 3,5 -an-hydroadenosine is observed. ... 

In contrast to the synthesis of purines, the synthesis of purine nucleosides from glycosylated pyrimidinediamines is less common than from glycosylated imidazoles. The synthesis protocol follows that of simple purines. A one-carbon unit is introduced into a 4-(glycosylamino)-pyrimidin-5-amine by selective thioformylalion of the 5-amino group with subsequent cycliza-tion of the 5-thioformamido compound under basic conditions, e.g. the sequence 4 5 -> 6. ... 

Nucleobase anion glycosylation of 6-substituted purines yields the jV -nucleosides as the main products. The situation changes if 5-aminoimidazole-4-carbonitrile instead of a purine is used as a precursor, then 4-amino-l-(ribofuranosyl)imidazole-5-carbonitrile (AICN-riboside) is formed as the main product and the N3 regioisomer as a minor component. For this reason imidazole nucleosides are very useful intermediates, especially for the synthesis of N7 glycosylated purines,... 

Strepikheev, Y.A., Khokhlov, P.S., and Kashemirov, B.A., Synthesis of oximinocyanomethylphospho-nates, Zh. Obshch. Khim., 51, 1206. 1981 Gen. Chem. USSR (Engl. Transl.), 51, 1020, 1981. Buchanan, J.G., McCaig, A.E., and Wightman, R.H., The synthesis of 4-alkylsulphonyl-5-amino- and 5-amino-4-phosphono-imidazole nucleosides as potential inhibitors of purine biosynthesis, J. Chem. Soc., Perkin Trans. 1, 955, 1990. 

Imidazole ring formation of acyclo C-nucleoside 543 was made by reaction of 6-chloro-l,3-dimethyl-5-nitrouracil with o-glucopyranosylamine (541), followed by catalytic hydrogenation and concomitant cyclization of 542 (67CB492). The same C-nucleoside (543) was obtained by reacting 1-amino-l-deoxy-D-glucitol (544) with 6-chloro-l,3-dimethyluracil and subsequent nitrosation and cyclization (96S459) (Scheme 145). 

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