6-Azauracil nucleosides

Azauridine was also synthesized using the knowledge of the course of alkylation of 6-azauracil 2-methylmercapto derivatives (e.g., Section II,B,4,b). The 1-ribofuranosyl derivative obtained by reaction of the mercury salt of the 2-methylmercapto derivative with tri-O-benzoyl-jS-D-ribofuranosyl chloride on removal of the methyl-mercapto and then benzoyl groups yielded crystalline 6-azauridine, The main difference between uracil and 6-azauracil nucleosides consists in the preparation of cyclic nucleosides. It is known that uridine can be readily converted to cyclic nucleosides by the reaction of 2 (50-O-mesyl derivatives with nucleophilic agents, Analogous... 

A few attempts have been made to observe the n tt transitions in uracils. No Cotton effect derived from an n tt transition is observed in the CD spectrum of uridine. Such transitions are observed in some 6-azauracil nucleosides, but they are located at the long-wavelength side of the first band (Ban). On the other hand, Eaton and... 

Azauracil nucleosides adopt an A-conformation, but nevertheless they are destabilising when incorporated into duplex DNA. Thermal de-naturation studies substituting thymidine with pseudothymidine showed that multiple incorporations had little effect in duplex stability. Moreover, up to four consecutive substitutions by pseudothymidine could be tolerated by DNA polymerases. ... 

As regards hexopyranosyl systems, 5-substituted-6-azauracil nucleosides of N acetylglucosamine have been prepared, and acetobromoglucose was used as starting material to make the bis(nitroimidazole) 71, in a search for hypoxia-selective antitumour agents with two bioreductively-activated units. ... 

Some of them were obtained for the first time by an enzymatic procedure which, of course, can result only in the aza analogs of natural nucleosides, i.e., ribofuranosyl-6-azauracil (6-azauridine) (75) and 2 -deoxyribofuranosyl-6-azathymine (6-azathymidine). The first of these was prepared by Skoda et ai. and a modification of their procedure was used by Handschumacher, In this way it is possible to obtain the crystalline nucleoside on the large scale. 

This synthesis appears to be quite general for the preparation of 1-substituted nucleosides and was used with small modifications for the synthesis of l-ribofuranosyl-6-azathymine and 2 -deoxyribo-furanosyl-6-azauracil and -6-azathymine. In the case of 2 -deoxy-ribofuranosyl a mixture of a- and )8-anomers is produced, their ratio depending on the reaction conditions. In the preparation of 2 -deoxy-ribofuranosyl-6-azathymine only one anomer was obtained having probably the )8-configuration, ... 

The deoxy analogs of 2.1 were prepared by coupling l-benzyloxy-2-chloromethoxypropane with silylated thymine, 6-azathymine, uracil, and 6-azauracil to give the anticipated nucleosides 1194 in addition to minor quantities of benzyloxymethylated produce 1195 of type 5.1 (94MI15). None of the deprotected nucleosides exhibited significant activity against HIV. 

Ketofucosyl nucleosides (38a and 38b) of 5-fluorouracil and 6-azauracil have been obtained39 from the partially protected L-fucosyl-pyrimidines 37a and 37b by oxidation with Me2SO-DCC and Ru04-CHC13, respectively. 

Very few compounds containing the 1,2,4-triazine moiety are found as natural materials, such as the pyrimido[5,4-c]-1,2,4-triazines, fervenulin (2),265 reumycin (3),265 toxoflavin (4) and MSD-92 (5).441 A large number of synthetic 1,2,4-triazines have biological activity and have been used for various purposes. Thus, 1,2,4-triazines can be considered as azapyrimidines and thus a large number of 6-azapyrimidine nucleotides and nucleosides have been prepared and their properties studied intensively, for example 6-azauracil (6), 6-azathymine(7), 6-azacytosine (8), 6-azauridine (9),442 and 6-azacytidine (10).443... 

Since 1,2,4-triazines can be considered as azapyrimidines, a great number of 6-azapyrimidine nucleotides and nucleosides have been prepared and their properties intensively studied. Most significant amongst these are 6-azauracil (1), 6-azauridine (2), 6-azathymine (3), 6-azacytosine (4) and 6-azacytidine (5). 

N-Alkylation of azauracils 189 with O-acylated bromobutenol affords acyclonucleosides 190 and 191 (Scheme 117), while N-glycosylation of 1,2,4-triazinones 192 results in the formation of nucleosides 193 (Scheme 118) <2005NN161>. 

In a similar manner, a number of abnormal nucleosides based on 5-azacytidine 194, 6-azacytidine 195, 6-azauracil (compounds 196-198) and azoloannelated 1,2,4-triazinones (compounds 199 and 200) have been obtained (Figure 10) <1996TL901, 2000BML2145, 2000JA10259, 2003JOC9012, 2005NN15>. 

A special subclass of amine formation reaction is the coupling of alcohols with purines to form nucleoside derivatives. The application of the Mitsunobu reaction in this context is sufficiently expansive to warrant a mini-review in its own right, but due to space constraints only a limited number of recent examples are shown below (195 - 198). "" The reader is referred to the references for additional information. Additional examples using iV -benzoylthymine, adenine, deazapurine, 6-azauracil, and 3-benzoyluracir have been reported in the literature as well. The preparation of racemic isonucleosides via the Mitsunobu reaction is also known. 

It is well established that aza analogs of purines, pyrimidines and their nucleosides possess significant but varying potency as antineoplastic agents [1-7]. Thus, for example, 6-azacytidine is an inhibitor for orotidylic acid decarboxylase [3] and 6-azauracil inhibits the development of animal tumors [4] and human acute leukemia [5] similarly, 8-azaguanine is a highly effective anti-neoplastic agent [6] and also inhibits animal tumors [7]. 

Cytidine has been converted into l-(5-amino-5-deoxy-j8-D-arabinofuranosyl) cytosine by a sequence of reactions involving A-benzoylation, sulphonation, acetylation, displacement with azide ion, e/c., and l-(3-amino-3-deoxy-jS-D-arabinofuranosyl)-6-azauracil was derived from 2, 3 -di-0-methanesulphonyl-5 -O-trityl-6-azauridine via 2,2 - and 2, 3 -anhydro-nucleosides. Other syntheses have been accomplished by the condensation of an appropriately derivatized amino-sugar with either a pyrimidine or purine derivative for example, the Hilbert route was used to prepare l-(2-amino-2-deoxy-a-D-arabino- and -jS-o-xylo-furanosyl)cytosine. > The reactivity of l,3,4,6-tetra-0-acetyl-2-acyl-amido-2-deoxy-j3-D-glucopyranoses in condensation reactions with 2,6-dichloro-purine, theophylline, and 6-benzylaminopurine was shown to be in the order benzamido > acetamido > phthalimido. 9-(3-Acetamido-2,5-di-0-acetyl-3-deoxy-j8-D-ribofuranosyl)-2,6-dichloropurine has been synthesized and converted into the corresponding 2,6-diamino- and 6-amino-2-chloro(fluoro)-nucleosides. ... 

Conventional condensation procedures have been used to prepare 2-pyridone nucleosides of type (7. i3 6-aza- and 2-thio-6-azauracil derivatives of type(8),i4 1-P-D-rlbofuranosyl derivatives of nltrobenzimidazoles, 15 chloroindazoles, and 6- and 7-p-chlorophenyllumazines,i and 2-... 

The reaction of 2,5-anhydro-3,4-0-isopropyIidene-DL-allose (450) (see Vol. 9, p. 22) with ethyl triphenylphosphoranylidene pyruvate at 90 °C gave the internal Michael-addition product (451) via the a)S-unsaturated ketoester formed in the Wittig reaction. Homo-C-nucleosides (452) containing 6-azauracil or 4-hydroxy-5-carboxamidopyrazole were elaborated from (451). Details of an earlier synthesis of the racemic hemiacetal (454), a precursor of carbocyclic C-nucleosides, have been published, together with an improved synthesis of (454) via the lactone (453) part of this route is outlined in Scheme 87. Condensation of the lactone... 

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