Pyrimidine nucleosides imidazoles

Nucleoside Pyrophosphates. - The synthesis of 8-aryl-3-P-o-ribofuranosylimiazo[2,l-i]purine 5 -phosphates (122) from AMP or ATP has been described. To access these fluorescent nucleotide derivatives, a combination of Kornblum oxidation reaction and imidazole formation was employed. For this conversion, the appropriate adenosine phosphate, present in its free acid form, was treated with p-nitro-acetophenone in DMSO in the presence of DBU. Treatment of a 5-(chloroethyl)-4-(triazole-l-yl)pyrimidine-nucleoside with benzylhydrazine offered the 6,6-bicyclic pyrimido-pyradazin-7-one, the precursor to (123). This triphosphate was used as a substrate for DNA polymerases. ... 

The naturally occurring nucleoside analogues discussed in this section contain the IV-glycosyl linkage and either purine, pyrimidine, imidazole, diazepin, or indole rings. The purine nucleosides inhibit protein synthesis, RNA and DNA synthesis, and methyltransferases they have antimycoplasmal, antiviral, hypotensive, antifungal, antimycobacterial, and antitumor activities and induce sporulation (1—4). The pyrimidine nucleosides inhibit protein synthesis, virus replication, RNA and DNA synthesis, and cAMP phosphodiesterase. The imidazole nucleosides inhibit nucleic acid synthesis. The diazepin nucleosides inhibit adenosine deaminase (ADA). The indole nucleosides inhibit bacteria, yeast, fungi, and viruses. 

R. Carrington, G. Shaw, and W. Wilson, Purines, pyrimidines and imidazoles. XXIII. The use of P-D-ribosyl azide 5-phosphate in a new direct synthesis of nucleosides, J. Chem. Soc., 1965, 6864-6870. 

Guo and co-workers reported a highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with p-nucleobase-substituted acrylates as dipolarophiles using 1 mol% of a chiral Cu(I) complex, which provides the first rapid and divergent access to various enantioenriched azacyclic nucleoside analogues in high yields with excellent exo-selectivities and enantioselectivities (Scheme 8) [19]. In addition, other p-heteroarylacrylates such as pyrimidine-, benzimidazole-, imidazole-, benzotriazole-, and indole-substituted acrylates are also suitable... 

The preparation of purines via an appropriate pyrimidine dominated the synthetic chemistry of purine especially in the early pre Second World War literature. The reason for this is undoubtedly connected with the difficulty of obtaining suitable imidazole, compared with pyrimidine, precursors and additionally by the tendency of imidazole precursors to be rather labile and prone to aerial oxidation. To some extent these disadvantages have been overcome in recent years and this particular route to purines including nucleosides and nucleotides has been used increasingly. The method of course is of special significance in that it is the route adopted in living systems for the de novo biosynthesis of purine nucleotides, and interestingly it also appears to be the route favoured in the so-called abiotic syntheses from simple acyclic precursors (see Section 4.09.8.1). 

Purines show typical absorption spectra which are useful for the identification and the determination of their structure tautomeric equilibria can also be studied. By comparison of the spectra of natural and synthetic derivatives of purines, the N9 glycosylic linkage was established for nucleosides. The relatively simple spectra of purines show two main bands. Purine shows maxima around 220 nm and at 263 nm in neutral solution. Since the imidazole ring has no characteristic UV absorption, the spectra of purines and pyrimidines show similarities. Similar observations have been made for 7-deazapurines, 8-azapurines etc. In the series of adenine hypoxanthine, and xanthine (at pH 6) only one maximum is observed guanine, isoguanine, and purinc-2,6-diamine show two maxima. 

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. ... 

Except for silylated pyrimidine and purine bases, silylated imidazoles and tri-methylsilylazide undergo similar glycosidation in the presence of la, leading to a variety of nucleoside precursors or analogs [74]. As first reported by Isono, la and 6a are also effective Lewis acids in the transglycosidation of pyrimidine 65 to afford adenine nucleoside 67 (Sch. 44) [75]. 

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... 

Uracil nucleosides react with 1-methylimidazole in the presence of phosphoryl chloride to give 4-substituted pyrimidin-2-(l/()-one nucleosides via quaternized imidazole species <85CPB2575>. Quaternary salts are believed to be intermediates in the thermal isomerization of 5- to 4-nitroimidazoles in the presence of catalytic quantities of iodomethane (Scheme 12) <88TL536i>. There is a similar transposition of l,2-dimethylimidazole-5-nitrile. 

The extreme alkali-lability of the imidazole ring of nebularine, which contrasts with the alkali-stability of the natural purine nucleosides previously discovered, has been noted and attributed to the lack of a stabilizing, tautomeric group in the 6-position of the pyrimidine ring. Related cases of this alkali-lability have been observed. ... 

Considering the scale of electron affinity of the different nucleosides, pyrimidine is found to be a much better electron acceptor than purine. On other hand, the purine bases, with the electron-rich imidazole, react with hydroxyl radical (OH ) faster than the electron-deficient pyrimidine [127]. This fact reflected the electrophilic nature of the hydroxyl radical. 

In addition to metabolizing some aldehydes, aldehyde oxidase also oxidizes a variety of azaheterocycles but not thia- or oxaheterocycles. Of the various purine nucleosides metabolized by aldehyde oxidase, the 2-hydroxy- and 2-amino derivatives are more efficiently metabolized, and for the N -substituents, the typical order of preference is the acyclic nucleosides is as follows 9-[(hydroxy-alkyloxy)methyl]-purines) > 2 -deoxyribofuranosyl > ribofuranosyl > arabinofuranosyl > H. The kinetic rate constants for purine analogues revealed that the pyrimidine portion of the purine ring system is more important for substrate affinity than the imidazole portion. Aldehyde oxidase is inhibited by potassium cyanide and menadione (synthetic vitamin K). 

These principles apply in bicyclic and multicychc systems as well, and large numbers of stable, aromatic systems are known. One of the most important bicyclic ring systems is that of purine, which is present among the bases of nucleic acids (Chapter 3). Here, a pyrimidine ring and an imidazole ring are fused. The latter will exhibit its usual tautomeric behavior, but now the two forms are not equivalent, and in purine itself form 7.15 is known to predominate over 7.16. In the nucleoside component of the nucleic acids (and in other compounds), the bond to the sugar moiety is located at the NH of form 7.15 (incorrectly but historically labeled the 9-position). 

C9H 3N50(, Mr 287.23, cryst., mp. 228-231 °C. Insecticidal nucleoside from the tawny funnel cap Clitocybe inverse, Basidiomycetes). The nitro group on the pyrimidine ring is an unusual feature it is presumably formed by oxidative cleavage from the imidazole ring of adenine. 

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